Rare liver diseases are associated with diagnostic delay, fragmented care, inconsistent management, and limited patient support. Patient pathways may help address these challenges by translating clinical guidance and patient priorities into practical, coordinated care processes. This manuscript presents a European template for developing patient-centred pathways for rare liver diseases within ERN RARE-LIVER. The template was developed through multidisciplinary collaboration involving hepatologists, specialist nurses, patient representatives, patient organisations, and EURORDIS, and was informed by clinical guidance, patient-journey principles, and iterative expert and patient review. The proposed framework follows four phases of the patient journey: pre-diagnosis, diagnosis, management, and long-term follow-up. It includes disease-specific sections, educational resources, frequently asked questions, and “10 key questions” to support shared decision-making. Pathways for non-cirrhotic portal vein thrombosis, polycystic liver disease, and portosinusoidal vascular disorder illustrate the practical application of the template. This European template provides a practical, adaptable framework aimed at supporting harmonised, multidisciplinary, and patient-centred care for rare liver diseases across European healthcare settings. Future work should evaluate implementation, usability, and impact on care coordination and patient experience.

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency or inborn error of immunity (IEI) encountered in clinical practice. Characterized by a remarkably broad clinical spectrum, CVID presents with phenotypes spanning from "infection only" to significant non-infectious complications. The frequent overlap between these classifications underscores that their distinction is more accurately viewed as a continuous spectrum, rather than a binary categorization. CVID-associated liver disease is a significant source of morbidity, yet often poses diagnostic challenges due to its insidious and clinically silent nature, typically becoming apparent only upon the development of complications. Manifestations range from abnormal liver tests to irreversible organ damage, with reports including granulomas, autoimmune hepatitis, fibrosis, and porto-sinusoidal vascular disorder (PSVD). Regenerative nodular hyperplasia (RNH), commonly associated with PSVD, is a frequent histopathological finding. Management requires a multidisciplinary approach, including cause-directed immunosuppression and supportive treatment for non-cirrhotic portal hypertension. Despite significant advances in comprehending CVID-associated liver involvement, substantial gaps persist concerning its pathogenesis, its optimal management, and the correlation between histological findings and clinical outcomes. A heightened awareness of CVID-associated liver disease is paramount for multidisciplinary teams across IEI centers. Furthermore, given its prevalence, its insidious clinical phenotype until advanced complications, and the significant diagnostic delay and underdiagnosis, such awareness is critical across a broader range of medical specialties. In this paper, we aim to consolidate current knowledge regarding CVID-related liver disease, examining its clinical presentation, recent genetic and pathogenetic advancements along with current diagnostic methodologies, and therapeutic strategies.

BACKGROUND & AIMS:Patients with non-cirrhotic non-tumoral portal venous system thrombosis (NCNT-PVT) require long-term anticoagulation to prevent rethrombosis (either splanchnic or at any site, referred to as overall rethrombosis - oRT) when there is an underlying high-risk thrombophilic disorder or history of previous thrombotic episodes. However, up to 25% of patients without such indications still develop oRT. Elevated factor VIII (≥150%), D-dimer (≥500 ng/ml) or the presence of high molecular risk (HMR) variants have been proposed as risk predictors for oRT in these patients. This study aimed to compare the prognostic value of these three biomarkers in a cohort of patients with NCNT-PVT. METHODS:We performed a multicenter, retrospective, observational study including 123 patients with NCNT-PVT without an indication for long-term anticoagulation. RESULTS:During a median follow-up of 89.3 months (IQR 36-129), 33 patients (27%) developed venous oRT, with a cumulative incidence of 7%, 17% and 26% at 1, 5 and 10 years. Factor VIII ≥150% and HMR were associated with oRT risk (hazard ratio 5.92, 95% CI 2.67-13.15, p <0.01; and hazard ratio 2.07, 95% CI 1.01-4.24, p = 0.04, respectively) while D-dimer ≥500 ng/ml showed a non-significant trend. Multivariate analysis confirmed factor VIII and HMR as independent predictors. CONCLUSIONS:Patients with unprovoked or local factor-associated PVT have a clinically relevant long-term risk of recurrence, with a 25% cumulative incidence of oRT at 10 years. Elevated factor VIII (≥150%) identifies a subgroup at particularly increased risk, and its combination with HMR variants may further refine risk stratification. IMPACT AND IMPLICATIONS:This study addresses an important clinical gap by evaluating whether prothrombotic and genetic biomarkers can help identify patients with non-cirrhotic, non-tumoral portal vein thrombosis who remain at risk of recurrent thrombosis despite the absence of classical thrombophilia. Our results show that persistently elevated factor VIII levels, alone or combined with high molecular risk variants, are strong predictors of rethrombosis in this population. These findings may help refine recurrence-risk stratification in patients traditionally considered low risk and could support more individualized decisions regarding long-term anticoagulation and follow-up intensity.

Background & Aims Liver (LSM) and spleen (SSM) stiffness measurements correlate with hepatic venous pressure gradient (HVPG), the reference standard for defining clinically significant portal hypertension (CSPH, i.e. HVPG ≥10 mmHg). LSM, SSM and derived scores have been proposed for non-invasive CSPH risk assessment. Methods Compensated advanced chronic liver disease (cACLD) patients undergoing same-day HVPG, Supersonic (SSI)-LSM, and SSI-SSM were prospectively included. Reliable SSI-LSM and SSI-SSM were defined by IQR/Med ≤30%. SSI-LSM, SSI-SSM and derived Baveno VII rules, Anticipate-SSI, LPS-SSI, and the newly developed SSI-4PH (LSM/SSM, platelet count: PLT, BMI) model were evaluated in a derivation cohort (DeCo) and an external validation cohort (VaCo). Results The DeCo comprised 220 patients, paired reliable SSI-LSM/SSI-SSM measurements were available in 118 (53.6%) patients including 74.6% with CSPH. The VaCo comprised 86 eligible patients, of whom 73 (84.9%) had paired reliable measurements including 43.8% with CSPH.In reliable paired analyses, AUROCs for CSPH detection in the DeCo were 0.84 for Anticipate-SSI, 0.87 for LPS-SSI, and 0.90 for SSI-4PH; the corresponding AUROCs in the VaCo were 0.78, 0.77, and 0.73. At the fixed ≥75% predicted-risk threshold, specificity of SSI-4PH was 83.3% in the DeCo and 87.8% in the VaCo. Conclusions Reliable SSI-LSM and SSI-SSM provide robust non-invasive assessment of CSPH risk, however, the requirement of reliable (IQR/Med ≤30%) paired measurements may limit applicability. Combined SSI-LSM/SSM-based rules and multivariable models reduced gray-zone, and the SSI-4PH yielded a favorable decision-curve utility for CSPH risk assessment.

Background:Sepsis is associated with high short-term mortality, particularly in patients with decompensated liver cirrhosis. Conventional inflammatory biomarkers have limited prognostic accuracy in this population. Presepsin has emerged as a promising biomarker; however, its dynamic behavior in early sepsis remains insufficiently characterized. Objectives:To evaluate the prognostic value of presepsin dynamics in sepsis, with and without underlying liver cirrhosis, and to compare it with established inflammatory markers. Methods:We conducted an observational cohort study including two patient groups: patients with sepsis and de-compensated liver cirrhosis (Group A) and patients with sepsis without cirrhosis (Group B). Presepsin levels were measured at admission and after 48 hours, and delta presepsin was calculated. Prognostic performance was assessed using receiver operating characteristic (ROC) analysis and Cox proportional hazards regression. The primary endpoint was 28-day mortality. Results:In Group A, presepsin measured at 48 hours demonstrated superior prognostic performance compared with baseline levels (AUROC 0.91 vs. 0.78). Changes in presepsin further enhanced risk stratification, with a negative delta associated with improved survival, whereas an increase of ≥500 pg/mL was independently associated with higher mortality. (HR 5, 95% CI:1.64-15.26). In Group B presepsin showed moderate prognostic performance at baseline and 48 hours, whereas delta presepsin demonstrated limited overall accuracy, except in patients with positive delta values. Established biomarkers, including C-reactive protein and procalcitonin, showed inferior prognostic performance compared with presepsin in both cohorts. Conclusions:Dynamic assessment of presepsin provides clinically relevant prognostic information in sepsis, particularly in patients with decompensated liver cirrhosis. Early changes in presepsin levels may enhance risk stratification beyond conventional inflammatory biomarkers.

AIMS:To assess whether contrast-enhanced ultrasound (CEUS)-derived intrahepatic transit times predict short-term hepatic decompensation in patients with compensated cirrhosis and to determine whether they provide incremental prognostic value over noninvasive markers. MATERIALS AND METHODS:In this prospective study, 46 patients with compensated cirrhosis underwent CEUS with time-intensity curve analysis to determine hepatic artery-to-hepatic vein (HA-HVTT) and portal vein-to-hepatic vein (PV-HVTT) transit times. Liver stiffness and clinical scores (MELD, MELD 3.0, Child-Pugh, ALBI, FIB-4) were recorded. Patients were followed for 180 days to assess decompensation (ascites, variceal bleeding, or encephalopathy). Diagnostic performance was evaluated using ROC analysis, and prognostic value was assessed using Cox regression. RESULTS:Twenty-three patients developed decompensation. PV-HVTT and HA-HVTT were significantly shorter in patients who decompensated (p<0.001). PV-HVTT showed excellent discrimination (AUC 0.928), outperforming liver stiffness and clinical scores (all p<0.01). A PV-HVTT cutoff of 2.38 seconds identified high-risk patients with a 6-month decompensation rate of 83.3%, compared with 13.6% in low-risk patients. PV-HVTT independently predicted decompensation (HR 0.37 per 0.5 s increase, p<0.001). HA-HVTT showed moderate performance. CONCLUSIONS:CEUS-derived transit times predict short-term decompensation in compensated cirrhosis and outperform established noninvasive markers. CEUS provides a functional assessment of intrahepatic hemodynamics and may improve risk stratification.

Primary liver cancer, of which hepatocellular carcinoma (HCC) represents the vast majority, is on the rise globally. Despite an expected decrease in viral hepatitis-related HCCs, the number of new cases and deaths from liver cancer is predicted to increase by over 30% in 2050 in Europe. This is largely driven by an increase in metabolic dysfunction-associated steatotic liver disease-related HCC and an aging population. Since HCC usually develops in patients with underlying chronic liver disease, over half of all cases appear to be preventable by targeting modifiable risk factors. This series paper summarizes epidemiological and etiological trends of HCC in Europe and their implications for the clinical management of HCC across different disease stages. We discuss public health initiatives and policies to counteract the rising incidence of HCC by focusing on prevention, and highlight additional benefits of etiological treatment for the management and prognosis of patients with HCC.

Background:Endoscopic ultrasound (EUS) has emerged as a valuable tool for assessing portal hypertension (PH). Our study aimed to compare endoscopic ultrasound-guided portal pressure gradient (EUS-PPG) with directly measured transjugular PPG (T-PPG) and hepatic venous pressure gradient (HVPG) during transjugular intrahepatic portosystemic shunt (TIPS). Methods:Consecutive patients scheduled for elective TIPS between March 2023 and December 2024 were included. EUS was performed using a 22-gauge FNA needle attached to an invasive pressure monitoring module. TIPS placement and HVPG were performed according to the standard methods. Results:Twenty-four patients who underwent elective TIPS for PH-related complications were enrolled (mean age 56.4 ± 8.8 years, model of end-stage liver disease [MELD] 15.0 ± 5.5). The technical success rates for EUS-PPG and HVPG were 92.3% and 100%, respectively. There was a strong correlation between EUS-PPG and T-PPG (r = 0.88, P < 0.01; intra-class correlation coefficient [ICC] = 0.930, 95% CI 0.837-0.970) and a moderate correlation between EUS-PPG and HVPG (r = 0.58, P < 0.05; ICC = 0.735, 95% CI 0.311-0.898). The presence of portal vein thrombosis (PVT) was independently associated with a ≥ 3 mmHg difference between EUS-PPG and T-PPG (P = 0.04). Child-Pugh score was independently associated with a ≥ 3 mmHg difference between EUS-PPG and HVPG (P = 0.01). Two minor adverse effects were reported. Conclusion:EUS-PPG demonstrates strong reliability when compared to direct PPG measurements obtained during TIPS insertion. Using a 22-gauge needle, EUS-PPG proved to be accurate and safe for assessing PH. The presence of PVT may be a cofounder of discrepancy between the direct methods.