Background-Aim: Primary biliary cholangitis (PBC) is a rare autoimmune liver disease. Epidemiological data in Italy are limited. To address this the Italian PBC Registry was established in 2019 to collect retrospective and prospective data. This study provides an overview of the Registry and its collected data.Methods: The Registry is based on a centralized database collecting demographics, biochemistry, disease stage and treatments. Tests at diagnosis were defined as those performed 3 months before to 30 days after diagnosis; tests at 1 year after UDCA were those performed 11–15 months after treatment initiation. Categorical variables are reported as frequencies (%); continuous variables are reported as mean ± SD or median and interquartile range (IQR). ALP, AST, ALT, GGT are expressed as ratios of their ULN, bilirubin as mg/dL.Results: From 2019 to 2025 enrolment increased from 128 to 3310 (37±22 patients/month). 3199 were analyzed (111 excluded for missing data). The Registry involves 69 active centers, 61 entering data, distributed across Italy (40 North, 9 Center, 20 South/Islands). 2836 (89%) were female with mean age 55.3 ± 12 years, BMI 24.96 ± 4.64, 3067 (96.7%) were Caucasian. Median follow-up was 6.9 years [3.1, 12.6]. 2018 (80.3%) reported no alcohol consumption, 456 (18.1%) consumed < 10/20 g/day (women/men) and 40 (1.6%) consumed >10/20 g/day (women/men). 1724 (70%) never smoked, 423 (17.2%) were former and 315 (12.8%) were current smokers. Optional biological samples (blood, urine, stool, liver tissue) are collected; 13 centers collect blood annually (recruitment/follow-up): 422 patients provided one sample, 116 two and 105 three or more. At diagnosis, among 1840 patients (57.5%) with available tests, the mean values were: ALP 1.59 [1.07, 2.67], AST 1.25 [0.83, 2.10], ALT 1.32 [0.80, 2.18], GGT 3.90 [1.89, 7.49], bilirubin 0.65 [0.50, 0.92] mg/dL. AMA positivity was detected in 1241 (68.5%), while 243 (13.4%) were negative and 328 (18.1%) had not been tested. Liver biopsy was performed in 666 (20.8%) patients and transient elastography in 653 (20.4%) with a median liver stiffness of 6.6 kPa [5.0, 9.1]. After one year of UDCA 809 (25.3%) patients had: ALP 1.11 [0.78, 1.64], AST 0.78 [0.59, 1.06], ALT 0.70 [0.48, 1.10], GGT 1.26 [0.70, 2.78], bilirubin 0.60 [0.44, 0.83] mg/dL. Elevated ALP (>1.67) was observed in 185 (22.9%) patients. However, considering the entire cohort, 923 (28.8%) patients initiated second-line therapy: 429 (46.5%) with Obeticholic Acid (OCA), 277 (30%) with fibrates (bezafibrate/fenofibrate), 163 (17.7%) with combination therapy (OCA and fibrate). Regarding the new PPAR-targeted therapies, 125 (13.5%) patients initiated Elafibranor and 52 (5.6%) initiated Seladelpar.Conclusions: The Italian PBC Registry provides a national picture of PBC, supporting disease monitoring and management. Continued commitment from participating centers will enhance data completeness and strengthen the reliability of future analyses.

Background & Aims: Several studies have assessed the short-term effectiveness and safety of obeticholic acid (OCA) in the real-world setting. We aimed to extend knowledge on the real-world effectiveness and safety of OCA treatment by expanding sample size and follow-up, and by exploring changes in liver stiffness measurement (LSM) over time. Methods: The RECAPITULATE project involves centres belonging to the “Italian PBC registry” and/or the “Club Epatologi Ospedalieri” PBC working group. Effectiveness was evaluated as biochemical response according to POISE and normal range (NR) criteria (normal alkaline phosphatase/alanine aminotransferase/bilirubin). Safety was assessed as the incidence of de novo/worsening pruritus and discontinuation rate/causes. Available LSMs were also captured. Results: We included 747 patients from 66 Italian centres: mean age 58 years; female/male 88%/14%; median follow-up 24 months [IQR 12-42]; 28% with cirrhosis, and 14% with autoimmune hepatitis (AIH)/PBC overlap syndrome. Probabilities of POISE and NR response increased from baseline to 57% and 20%, respectively, by the 42nd month. The probabilities of response were lower in patients with cirrhosis (p = 0.02 and p = 0.004 for POISE and NR), but not different between patients with AIH/PBC and pure PBC (p = 0.8). Overall, 130 patients (17%) discontinued treatment, mainly due to pruritus (36.9%), while 28.5% did so after developing hepatic events. The discontinuation rate was higher in patients with cirrhosis (p <0.001). LSM was available in 573 patients (∼77%), of whom 255 had multiple measurements. LSM variation over time differed based on the attainment of POISE biochemical response (expected mean annual variation -0.48 [-0.78, -0.19] in responders vs. +0.33 [-0.07, 0.73] in non-responders, respectively, p <0.001). Conclusions: Our findings confirm the effectiveness and safety profiles of OCA in the medium/long term and demonstrate that biochemical response is associated with the change in LSM over time. Impact and Implications: After the conditional approval of OCA for the treatment of PBC, the main confirmatory study failed to demonstrate OCA's ability to reduce liver-related events, leading the EMA to revoke the drug's marketing authorization. The ensuing scientific debate highlights an urgent need for further evidence from real-world practice. In the largest real-world series of patients treated with OCA to date, we confirm that the drug's effectiveness and safety profiles are maintained over a medium-to-long follow-up period. Valuable data for the management of the drug in relevant subgroups of patients, such as those with cirrhosis and autoimmune hepatitis/PBC overlap syndrome, are also provided. Our original results on liver stiffness measurement variation over time suggest a favourable impact of OCA on fibrosis progression, particularly in patients achieving a biochemical response to the drug. Overall, these data provide important insights for clinicians managing patients with PBC and contribute to the ongoing scientific debate about the effectiveness/safety profile of this drug.

Hepatocellular carcinoma (HCC) is the sixth most common cancer globally and the third leading cause of cancer-related mortality, primarily driven by viral infections (HCV, HBV) and steatotic liver diseases (SLD). Despite advances in treatment, early detection and accurate prognosis remain challenging. The Human leukocyte antigen G (HLA-G) molecule is dysregulated in various conditions, including cancers and viral infections. This study aimed to investigate HLA-G’s role in viral-related and SLD-driven HCC. We analyzed a cohort of 116 HCC patients and 140 healthy controls to assess HLA-G genetic variants and soluble levels. Results showed significantly higher levels of soluble HLA-G in HCC patients compared to controls (Pc = 0.003). Moreover, overall survival (OS) was significantly lower in patients with the extended HLA-G*01:01:01/UTR-1 haplotype (Log-rank test, p = 0.002), a trend consistent in both HCV and/or HBV-related HCC (p = 0.025) and SLD-related HCC (p = 0.018). Elevated sHLA-G levels were associated with shorter OS across both subgroups (p = 0.034 (HBV/HCV) and p = 0.010 (SLD), respectively). The findings suggest that elevated levels of soluble HLA-G and specific genetic variants are associated with poor prognosis in HCC patients, highlighting the potential of HLA-G as a prognostic biomarker in both viral-related and steatotic liver disease-related HCC.

BACKGROUND AND AIMS:Hepatitis B (HBV) and Hepatitis Delta virus (HDV) infection have undergone significant changes in Italy over the past few decades, but reliable and updated prevalence of chronic hepatitis B (CHB) and Delta (CHD) data are lacking. The aim of the study was to describe the epidemiology of CHB and CHD in Italy in 2024, based on real-world data. METHODS:The number of patients with a healthcare expenditure exemption for CHB (016.070.32) and CHD (016.070.33) was obtained from 21 Regional Health Authorities. To understand how many CHB or CHD patients did not have these specific exemptions, a survey was conducted in 30 Gastroenterology, Hepatology and Infectious Diseases Units across the country. RESULTS:Health Authorities data reported 67 514 and 5216 subjects with an exemption for CHB and for CHD, respectively. However, among 6775 CHB and 504 CHD patients, only 60.3% and 55.7% of them had the specific exemption, respectively. Based on these results, we estimated 111 960 (95% CI: 109 780-114 240) CHB and 9360 (95% CI: 8690-10 150) CHD patients, with a prevalence of 0.22% and 0.019% of the adult overall population. Moreover, anti-HDV prevalence was 7.7% from this cohort. CONCLUSION:Our study provides a plausible estimate of the current number of adult patients diagnosed with CHB and CHD in Italy and may be considered the basis for decision-making health policies.

INTRODUCTION:A reliable quantification of hepatitis D virus (HDV) RNA is of paramount importance for monitoring patients under antiviral therapy. This quality control study compares the diagnostic performances of quantitative HDV-RNA assays used in clinical practice. METHODS:Two HDV-RNA sample panels were quantified in 30 centers by RoboGene (N = 9 laboratories), EurobioPlex (N = 7), RealStar (N = 4), AltoStar (N = 1), Bosphore (N = 3), Bosphore-on-InGenius (N = 1), Dia.Pro (N = 2), Nuclear-Laser-Medicine (N = 1) and 3 in-house assays. Panel A and B comprised 8 serial dilutions of WHO/HDV standard (range: 0.5-5.0 log10 IU/ml) and 20 clinical samples (range: 0.5-6.0 log10 IU/ml), respectively. The following parameters were determined: sensitivity by 95 % LOD (limit of detection), precision by intra- and inter-run CV (coefficient of variation), accuracy by the differences between expected-observed HDV-RNA, linearity by linear regression analysis. RESULTS:95 % LOD varied across assays and centers underlining heterogeneous sensitivities: AltoStar had the lowest 95 % LOD (3 IU/ml) followed by RealStar (10 [min-max: 3-316] IU/ml), Bosphore-on-InGenius (10 IU/ml), RoboGene (31 [3-316] IU/ml), Nuclear-Laser-Medicine (31 IU/ml) and EuroBioplex (100 [100-316] IU/ml). Moreover, 6 assays (RoboGene, EurobioPlex, RealStar, AltoStar, Nuclear-Laser-Medicine and In-house) showed <0.5 log10 IU/ml differences between expected and observed HDV-RNA for all dilutions while other assays had >1 log10 IU/ml underestimations. RealStar, Bosphore-on-InGenius and EurobioPlex had the highest precision (mean intra-run CV < 20 %). Inter-run CV was higher for all assays, with CVs < 25 % for RealStar, AltoStar, Nuclear-Laser-Medicine and EurobioPlex. Seven assays (RoboGene/AltoStar/RealStar/EurobioPlex/Nuclear-Laser-Medicine/In-house) showed a good linearity (R2 > 0.90), but for HDV-RNA < 1000 IU/ml only Bosphore-on-InGenius, AltoStar, RealStar and Robogene showed a R2 > 0.85. CONCLUSIONS:This study underlines heterogeneous sensitivities (inter- and intraassays), that could hamper proper HDV-RNA quantification, particularly at low viral loads. This raises the need to improve the diagnostic performance of most assays for properly identifying virological response to anti-HDV drugs.

Introduction:Primary biliary cholangitis (PBC) is a rare autoimmune liver disease involving bile duct damage and fibrosis. This study explores the role of HLA-G, an immunomodulatory molecule crucial for immune tolerance, in PBC pathogenesis and treatment. Methods:A cohort of 166 PBC patients from Sardinia was compared to 180 healthy controls and 205 autoimmune hepatitis type 1 (AIH-1) patients. Plasma soluble HLA-G (sHLA-G) levels, HLA-G alleles, and 3'UTR haplotypes were analyzed alongside clinical data, including therapy response to ursodeoxycholic acid. Results:The UTR-1 haplotype was significantly more frequent in PBC patients than in controls (48.2% vs 34.3%, Pc= 0.0018). The extended haplotype HLA-G*01:01:01:08/UTR-1 was also strongly associated with PBC (23.2% vs 12.5% in controls, Pc = 0.008; 23.2% vs 6.6% in AIH-1, Pc= 2.6×10-9). PBC patients exhibited lower sHLA-G levels compared to controls and AIH-1 (9.1 U/mL vs 24.03 U/mL and 13.9 U/mL, respectively). Among UTR-1 carriers, sHLA-G levels were particularly reduced in PBC patients. The HLA-G*01:01:01:08/UTR-1 haplotype correlated with the lowest sHLA-G levels and poorer therapy response (60% vs 24.1%, P = 0.0001). Discussion:These findings suggest HLA-G variants, especially HLA-G*01:01:01:08/UTR-1, as potential biomarkers for PBC prognosis and treatment outcomes.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterized by the disruption of the alveolar and interstitial architecture due to extracellular matrix deposition. Emerging evidence suggests that genetic susceptibility plays a crucial role in IPF development. This study explores the role of human leukocyte antigen (HLA) alleles and haplotypes in IPF susceptibility and progression within the genetically distinct Sardinian population. Genotypic data were analyzed for associations with disease onset and progression, focusing on allele and haplotype frequencies in patients exhibiting slow (S) or rapid (R) progression. While no significant differences in HLA allele frequencies were observed between IPF patients and controls, the HLA-DRB1*04:05 allele and the extended haplotype (HLA-A*30:02, B*18:01, C*05:01, DQA1*05:01, DQB1*02:01, DRB1*03:01) were associated with a slower disease progression and improved survival (log-rank = 0.032 and 0.01, respectively). At 36 months, carriers of these variants demonstrated significantly better pulmonary function, measured with single-breath carbon monoxide diffusing capacity (DLCO%p) (p = 0.005 and 0.02, respectively). Multivariate analysis confirmed these findings as being independent of confounding factors. These results highlight the impact of HLA alleles and haplotypes on IPF outcomes and underscore the potential of the Sardinian genetic landscape to illuminate immunological mechanisms, paving the way for predictive biomarkers and personalized therapies.

IntroductionWith the growing older adult population, the European Union emphasizes the need to promote research in healthy aging trough multidisciplinary and innovative approaches, including the integration of advanced technologies like virtual reality (VR) in cognitive rehabilitation. This reflects the increasing awareness of the importance of addressing challenges related to neurodegenerative diseases in the older adult population. Our study aims to present a protocol that will assess the feasibility and provide a preliminary measure of effectiveness for an intervention using immersive CR technology for cognitive remediation (CR) in individuals with Mild Cognitive Impairment (MCI).MethodsA feasibility randomized controlled clinical study will involve 30 individuals who are over 65 years old, both sex, who meet the diagnostic criteria for MCI from the University Hospital of Cagliari, randomly assigned to either the experimental condition or control group. Both groups will continue to receive standard pharmacological therapy. The experimental group will undergo a 3-months cognitive remediation program using fully immersive VR with two sessions per week. Each session will last a maximum of 60 min and will be supervised by expert health professionals. In contrast, the control group will continue with standard care. The intervention program will be carried out by s psychiatric rehabilitation technicians and speech therapists, emphasizing a comprehensive framework aligned with healthcare needs. Feasibility will be assessed based on tolerability, including dropout rates and acceptability, which considers the proportion of recruited participants among those considered eligible and on side effects and level of satisfaction. The preliminary measures of effectiveness will be evaluated on quality of life, cognitive functions, biological and social rhythms, depressive symptoms and anxiety.ResultsThe trial findings will be submitted for publication in international peer-reviewed journals and shared at international meetings and conferences.DiscussionThis study aiming to assess the feasibility and preliminary effectiveness of a fully immersive VR/CR program for MCI in order to give data for a subsequent confirmatory trial. The results of the pilot RCT are expected to significantly contribute to research on the prevention of neurocognitive degeneration, with a specific emphasis on enhancing the application of technologies. The strengths of this work are the high technological innovation program for mental health treatments for healthy aging and multidisciplinary approach emphasizing a holistic framework aligned with health needs.

IntroductionPrimary biliary cholangitis (PBC) is a rare autoimmune cholestatic liver disease. PBC has a mosaic pathogenesis, environmental factors probably interact with immunogenetic and epigenetic risk, favouring the development of the disease. The human leukocyte antigen-G (HLA-G) is one of the most significant tolerogenic system due to its immunosuppressive effects on all types of immune cells. Our previous studies have demonstrated that type 1 autoimmune hepatitis (AIH-1) patients had sHLA-G levels significantly lower than those in the control group, and lower levels are associated with a more severe disease. HLA has been extensively studied in PBC, however, to the best of our knowledge, the immunomodulatory effects of HLA-G expression and its role in PBC have not been investigated.AimIn this study we investigated the role of soluble HLA-G (sHLA-G) and whereas it could affect onset and therapy response in PBC patients.Materials and MethodsA cohort of 166 Sardinian PBC patients was compared to two groups, 180 healthy individuals and 205 AIH-1 patients. Soluble HLA-G levels were measured in patients and in healthy controls at the time of enrolment.ResultsReduced levels of sHLA-G were more frequently present in patients of our PBC group when compared to the other two groups, suggesting disease predisposition for those patients showing those characteristics [PBC 16.3 (3.5 – 29.1) U/mL vs Controls 24.3 (5.7 – 42.3) U/mL and vs AIH-1 24.3 (0.6 – 48) U/mL; P = 0.002]. Soluble HLA-G levels are significantly related to the therapy response, in fact among PBC patients those who do not reach an adequate therapy response have significantly lower sHLA-G levels compared to those with adequate response [15.53 (6.29 – 24.77) U/mL vs 25.58 (0.0 – 60.9) U/mL respectively; P = 0.010]ConclusionReduced levels of sHLA-G are involved in PBC onset and in therapy response.

Background & Aims: Sustained virological response (SVR) by direct-acting antivirals (DAAs) may reverse the hypercoagulable state of HCV cirrhosis and the portal vein thrombosis (PVT) risk. We evaluated the incidence and predictive factors of de novo, non-tumoral PVT in patients with cirrhosis after HCV eradication.Methods: Patients with HCV-related cirrhosis, consecutively enrolled in the multi-center ongoing PITER cohort, who achieved the SVR using DAAs, were prospectively evaluated. Kaplan-Meier and competing risk regression analyses were performed.Results: During a median time of 38.3 months (IQR: 25.1-48.7 months) after the end of treatment (EOT), among 1609 SVR patients, 32 (2.0%) developed de novo PVT. A platelet count <= 120,000/mu L, albumin levels <= 3.5 mg/dL, bilirubin >1.1 mg/dL, a previous liver decompensation, ALBI, Baveno, FIB-4, and RESIST scores were significantly different (p < 0.001), among patients who developed PVT versus those who did not. Considering death and liver transplantation as competing risk events, esophageal varices (subHR: 10.40; CI 95% 4.33-24.99) and pre-treatment ALBI grade >= 2 (subHR: 4.32; CI 95% 1.36-13.74) were independent predictors of PVT. After HCV eradication, a significant variation in PLT count, albumin, and bilirubin (p < 0.001) versus pre-treatment values was observed in patients who did not develop PVT, whereas no significant differences were observed in those who developed PVT (p > 0.05). After the EOT, esophageal varices and ALBI grade >= 2, remained associated with de novo PVT (subHR: 9.32; CI 95% 3.16-27.53 and subHR: 5.50; CI 95% 1.67-18.13, respectively).Conclusions: In patients with HCV-related cirrhosis, a more advanced liver disease and significant portal hypertension are independently associated with the de novo PVT risk after SVR.