BACKGROUND & AIMS:We report 104-week placebo-controlled data and long-term open-label extension (OLE) data from the ongoing ELATIVE® phase III trial (NCT04526665) of elafibranor in primary biliary cholangitis (PBC). METHODS:161 patients were randomized 2:1 to elafibranor 80 mg or placebo. The double-blind period (DBP) consisted of 52-week common (Part 1) and variable (Part 2) periods. Patients completing Part 1 continued into Part 2 until all patients completed Part 1, or for a maximum of 104 weeks. All patients completing Part 1 could enter the OLE and receive elafibranor. RESULTS:At Week 104 in the DBP Part 2, 64.3% (18/28) and 10.7% (3/28) of elafibranor-treated patients achieved biochemical response and alkaline phosphatase (ALP) normalization, versus no placebo-treated patients. In patients with moderate-to-severe fatigue or pruritus at baseline, mean (SE) changes to Week 104 in PROMIS Fatigue Short Form 7a (PFSF 7a) and PBC Worst-Itch Numeric Rating Scale (PBC WI NRS) were -6.3 (2.2) versus -0.4 (1.2) and -4.1 (1.0) versus 0.3 (1.2) with elafibranor versus placebo. 138 patients entered the OLE (continuous elafibranor: n=93; crossover elafibranor: n=45). In continuous patients at Weeks 104 and 156, 58.8% (47/80) and 65.0% (13/20) achieved biochemical response, and 15.0% (12/80) and 25.0% (5/20) achieved ALP normalization. In crossover patients, 51.2% (21/41) and 22.0% (9/41) achieved biochemical response and ALP normalization after 52 weeks. In continuous patients with baseline moderate-to-severe symptoms, mean (SE) changes to Week 130 in PFSF 7a and PBC WI NRS were -4.8 (1.5) and -4.0 (0.7). There were no unexpected safety findings. CONCLUSIONS:Through three years of treatment, elafibranor led to sustained biochemical improvements and was generally well tolerated, with numerical improvements in fatigue and pruritus. TRIAL REGISTRATION:NCT04526665 (https://clinicaltrials.gov/study/NCT04526665); first registered 08/26/2020 IMPACT AND IMPLICATIONS: • Given the chronic, progressive nature of primary biliary cholangitis (PBC), the long-term efficacy and tolerability of treatments is important.• Here, we present two-year results from the double-blind period, and long-term data from the ongoing open-label extension of the phase III ELATIVE® trial, wherein elafibranor (a peroxisome proliferator-activated receptor-α/δ agonist) treatment led to sustained biochemical improvements, stable non-invasive tests of fibrosis, and numerical improvements in fatigue and pruritus, through three years.• Elafibranor demonstrated a favorable safety profile up to a maximum treatment exposure of 3.5 years, including in patients crossing over from placebo.• These findings support elafibranor's role as a durable long-term treatment for patients with PBC, and are particularly relevant for clinicians managing patients with inadequate response or intolerance to first-line treatments.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease and shows a broad phenotypic spectrum, from simple steatosis to steatohepatitis (MASH), cirrhosis and MASH-related hepatocellular carcinoma. Identifying active disease with histological injury remains challenging, as reliable non-invasive tools for detecting MASH are still lacking. Lipidomics has emerged as a promising approach to characterise the metabolic disturbances underlying MASLD and MASH. Given the central role of lipid metabolism in disease pathogenesis, plasma lipid profiling may reveal stage-specific signatures useful for diagnosis and monitoring. This pilot study explores whether plasma lipidomic profiles can distinguish patients with MASH from those without.Methods: 14 consecutive patients at the Civil Hospital of Baggiovara undergoing liver biopsy for suspected MASH were enrolled. Plasma samples were collected on the day of biopsy. After lipid extraction, samples were analysed using ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-HRMS). Differential expression analyses compared plasma lipidomic signatures between patients with histologically confirmed MASH and those without.Results: Patients with MASH exhibited a distinct plasma lipidomic profile compared with non-MASH subjects. Multivariate analysis achieved clear separation between the groups and identified the lipid classes most responsible, offering insights into the metabolic pathways most affected. Ether-linked lipids emerged as the most significantly altered. MASH patients consistently showed reduced ether-linked phosphatidylcholines (PC O-) together with increased levels of several conventional phosphatidylcholines (PC). This opposite trend is notable because ether-linked species contribute to membrane stability and antioxidant defence; their depletion may therefore reflect early metabolic stress and greater hepatocellular vulnerability typical of steatohepatitis.Some non-MASH patients with advanced fibrosis displayed intermediate or atypical lipidomic patterns, suggesting that specific lipid alterations may precede inflammatory injury and help identify individuals at higher risk of progression. Despite the small cohort, these findings indicate that plasma lipidomics captures meaningful metabolic differences between MASH and non-MASH patients, highlighting phosphatidylcholines—especially ether-linked forms—as potential markers of early disease activity.Conclusions: This pilot study supports the utility of plasma lipidomics in detecting early metabolic changes associated with MASH. Larger studies integrating untargeted and targeted lipidomic/metabolomic approaches are needed to refine patient stratification, improve risk assessment and guide personalised interventions, advancing precision medicine in MASLD.

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.

Bulevirtide (BLV) is an entry inhibitor approved in Europe and Australia as a therapy for patients with chronic hepatitis delta (CHD); noninvasive tests (NITs) have demonstrated improvements in hepatic function and burden of liver disease with BLV treatment. Here we describe changes in NITs through up to 3 years of treatment.A longitudinal analysis was conducted using the Phase 3 MYR301 (NCT03852719) study data to determine the effect of BLV on results of alanine aminotransferase (ALT) level measurements and 3 NITs: fibrosis index based on 4 factors (FIB-4), aspartate aminotransferase to platelet ratio index (APRI), and liver stiffness measurement (LSM). In total, 150 patients with CHD were randomised to either no treatment for 48 weeks (W) followed by BLV 10 mg/d for 96W, or to BLV 2 or 10 mg/d for 144W. Change from baseline (BL) in NITs was assessed through 96W and 144W of treatment. This analysis was repeated for the pooled immediate treatment groups stratified by hepatitis delta virus (HDV) RNA response at W144: virologic responders (VR; undetectable HDV RNA or ≥ 2 log10 IU/mL decline in HDV RNA from BL), partial responders (PR; ≥ 1 log10 IU/mL but < 2 log10 IU/mL decline in HDV RNA from BL), and nonresponders (NR; < 1 log10 IU/mL decline in HDV RNA from BL). Patients with HDV RNA values missing at W144 were excluded. Results are reported as median (quartile [Q]1, Q3) unless otherwise stated.Overall, 149 patients with CHD were treated with BLV monotherapy (BLV 2 mg [n = 49]; BLV 10 mg [n = 100]); 99 were randomised to immediate BLV treatment for 144W, and 50 in the BLV 10 mg group received treatment for 96W. NITs showed improvements in all cohorts after 48W of therapy, which were maintained through 144W of therapy. Changes from BL at W144 were: BLV 2 mg group, FIB-4, −0.52 (−1.19, −0.03); LSM, −4.00 (−6.00, −1.00) kPa; immediate BLV 10 mg treatment group, FIB-4, −0.43 (−0.94, −0.14); LSM, −3.80 (−6.70, −1.20) kPa; and BLV delayed treatment group at W144 after 96W of treatment, FIB-4, −0.27 (−0.62, 0.02); LSM, −3.15 (−7.00, −0.40) kPa. Improvements at W144 in NITs were also seen across all viral response groups in the pooled immediate treatment cohort, including VR (n = 74), PR (n = 7), and NR (n = 8) at W144. Among VR, changes from BL were FIB-4, −0.43 (−1.05, −0.11); and LSM, −3.85 (−6.50, −1.20) kPa. Among PR, changes from BL were FIB-4, −0.39 (−0.48, −0.09); and LSM, −1.30 (−3.80, 0.20) kPa. Among NR, changes from BL were FIB-4, −1.02 (−1.60, −0.78); and LSM, −4.00 (−15.70, −1.10) kPa. Changes from BL in ALT levels and APRI scores were consistent with the trends observed in FIB-4 across all treatment cohorts. Treatment with BLV 2 or 10 mg monotherapy for up to 3 years resulted in longitudinal improvements in NITs in patients with CHD and were numerically greater with longer treatment duration. These improvements were seen even among the few patients without viral response.

BACKGROUND & AIMS:Bulevirtide is approved in several countries and regions for the treatment of compensated chronic hepatitis D (CHD). However, long-term outcomes after treatment discontinuation remain unknown. METHODS:Patients with CHD (n = 150) were randomized to immediate treatment with bulevirtide 2 mg/day (n = 49) or 10 mg/day (n = 50) for 144 weeks (W), or a 48W delay before starting treatment (DT; n = 51) followed by bulevirtide 10 mg/day for 96W (DT/10 mg; n = 50), and 96W of post-treatment follow-up (FU96) in the MYR301 study. Efficacy endpoints included virologic response (VR; undetectable HDV RNA or ≥2 log10 IU/ml decline from baseline), combined response (CR; VR and alanine aminotransferase [ALT] normalization), ALT normalization, and undetectable HDV RNA. RESULTS:At the end of treatment (EOT), response rates in the 2, 10, and DT/10 mg groups were: VR, 73%, 76%, and 92%; ALT normalization, 59%, 60%, and 58%; CR, 57%, 54%, and 56%; and HDV RNA undetectability, 29%, 50%, and 52%. At FU96, VR rates declined to 33%, 30%, and 32%, respectively; CR rates were 24% across all groups. HDV RNA undetectability rates were 20%, 22%, and 20% at FU96. Sustained undetectability through follow-up was observed in 23/64 (36%) patients with undetectable HDV RNA at EOT, with weeks continuously undetectable at EOT being the most important predictor of sustained undetectability. Post-treatment hepatic serious adverse events occurred in 20/142 (14%) patients and resolved in 17/20 (85%). CONCLUSIONS:Bulevirtide treatment for CHD for up to 144W was safe and effective. Response rates decreased after treatment discontinuation; however, some patients had sustained undetectable HDV RNA throughout 2 years of follow-up. IMPACT AND IMPLICATIONS:Although bulevirtide is approved for treatment of chronic hepatitis D (CHD) in several countries and regions including the United States, the European Economic Area, the United Kingdom, Switzerland, the Russian Federation, Australia, and Canada, treatment outcomes beyond 2 years and after bulevirtide discontinuation remain unknown. In this analysis, we demonstrate that efficacy was maintained with bulevirtide monotherapy for up to 144 weeks compared with that at 96 weeks, while rates of HDV RNA undetectability continued to improve with extended treatment duration. Virologic and biochemical responses decreased after treatment discontinuation, but some patients with undetectable HDV at the end of treatment maintained HDV RNA undetectability post-treatment, with duration of continuous HDV RNA undetectability at the end of treatment being the strongest predictor of non-relapse. While most patients benefit from continued bulevirtide therapy, a subset of those who achieve undetectable HDV RNA may be able to discontinue treatment without loss of response even in the absence of HBsAg loss. CLINICAL TRIAL NUMBER:NCT03852719.

Background and Objectives: Adult-onset cryptogenic cholestasis (AOCC) remains a diagnostic challenge. With the increasing use of Next-Generation Sequencing (NGS), variants in genes traditionally linked to paediatric cholestatic disorders are increasingly detected in adults. This study evaluated the diagnostic yield of a multigene panel and explored genotype–phenotype correlations in a large Italian AOCC cohort.METHODS:From February 2017 to May 2023, outpatients >14 years with AOCC were consecutively enrolled in four Italian tertiary centres. High-throughput sequencing covering up to 36 genes—including PFIC-related ATP8B1, ABCB11, ABCB4, TJP2, NR1H4, VPS33B, MYO5B, KIF12, SEMA7A, SLC51A, USP53, VPS39, ZFYVE19—was performed. Variants were classified following ACMG criteria. Clinical, biochemical, and histological features were compared between patients with pathogenic/likely pathogenic mutations (P/LPMs) and those without, considering both the whole panel and PFIC genes alone. RESULTS: A total of 233 patients were analysed; median age at testing was 46 years (35.0–55.0), and 108 (46.4%) were male. Serum bile acids (8; 4.0–18.8 μmol/L), γ-GT (97; 43.0–187.0 IU/L), and alkaline phosphatase (127.5; 92.0–187.0 U/L) showed mild elevation. Liver stiffness values indicated absent or minimal fibrosis (5.3; 4.3–7.3 kPa). P/LPMs were detected in 45 patients (19.3%); 106 (45.5%) carried either P/LPMs or VUS. Frequently affected genes were ABCB4, TJP2, SLCO1B3, ABCB11, MYO5B, ABCC2, VPS33B, and ATP8B1.Patients with P/LPMs more commonly had intrahepatic cholestasis of pregnancy (ICP), early-onset cholelithiasis, LPAC, a family history of liver disease, younger age (<40 years) and higher bile acids (p<0.05). The rate of P/LPMs in PFIC genes across the entire cohort was 15.5% (36 patients). In this subgroup, subjects more often reported ICP, LPAC, early cholelithiasis and familial liver disease, were younger at testing, and had higher alpha-fetoprotein values (p<0.05).Two multivariate models were developed. In the first, male sex (OR 4.065; 95% CI 1.564–10.568; p=0.004), bile acids (OR 1.016; 95% CI 1.001–1.032; p=0.044) and early-onset cholelithiasis (OR 2.412; 95% CI 1.000–5.959; p=0.050) independently predicted P/LPMs in the cholestasis panel. In the second, focusing on PFIC genes, ICP (OR 5.313; 95% CI 1.788–15.783; p=0.003) and early-onset cholelithiasis (OR 3.163; 95% CI 1.422–7.032; p=0.005) were the only independent predictors. CONCLUSIONS: Variants in inherited cholestasis genes are frequent in AOCC and associate with distinct phenotypes, particularly early-onset cholelithiasis and ICP, largely involving PFIC genes. ABCB4 remains the most commonly implicated gene. Integrating NGS into diagnostic pathways may improve recognition of genetic cholestatic disorders in adult hepatology.

Background and Objectives: Patients with obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome are at high risk of metabolic dysfunction-associated steatotic liver disease (MASLD), steatohepatitis (MASH), and advanced fibrosis. We assessed the prevalence and severity of MASLD and the diagnostic accuracy of a sequential algorithm using the Fibrosis-4 (Fib-4) index and liver stiffness (LS) measurement in a prospective cohort of patients with severe obesity, T2DM, and metabolic syndrome.Methods: Consecutive patients followed at the Civil Hospital of Baggiovara, University Hospital of Modena, underwent liver ultrasound for steatosis (SLD) detection, Controlled Attenuation Parameter (CAP) measurement via Fibroscan®, and LS evaluation using Fibroscan® and 2D-Shear Wave Elastography (2D-SWE).Results: Among 218 patients (median age 54.6 [43.9–61.8] years; 47.7% male), obesity, T2DM, hypertension, and dyslipidemia were present in 83.5%, 29.4%, 51.8%, and 63.3%, respectively.SLD, defined as ultrasound-detected steatosis and/or CAP ≥248 dB/m, was found in 188 (86.2%) cases, with MASLD as the cause in 95.7%. Advanced fibrosis (LS ≥8 kPa by Fibroscan® or ≥8 kPa by 2D-SWE in case of failure, 5.0%) was detected in 50 patients (22.9%). Fibrosis correlated with male sex (p<0.001), BMI (p=0.007), systolic BP (p=0.019), HOMA-IR (p=0.005), AST, ALT, GGT (all p<0.001), and SLD (p=0.022), and inversely with LDL (p=0.028) and HDL cholesterol (p=0.014).Application of the 2024 EASL-EASD-EASO algorithm (Fib-4 + LS) achieved 82.6% diagnostic accuracy, identifying 20 patients (9.2%) needing hepatology referral (8 with Fib-4 ≥2.67; 12/37 with Fib-4 1.3/2.0–2.67 and LS ≥8 kPa) and 198 (90.8%) not requiring it. Among 173 low-risk patients (Fib-4 <1.3/2.0), 34 (19.7%) had LS ≥8 kPa; they were more frequently male, younger, severely obese (BMI >40 kg/m²), and had higher ALT, SBP, and SLD prevalence. On multivariate analysis, male sex [OR 3.82 (1.48–9.85), p=0.006] and BMI >40 kg/m² [OR 4.13 (1.54–11.09), p=0.005] were independently associated with LS ≥8 kPa.A stricter advanced fibrosis definition (LS ≥8 kPa on both methods, 12 patients, 5.9%) improved accuracy to 95.1%, with only 5/161 (3.1%) low-risk cases showing LS ≥8 kPa, suggesting single-method overestimation. Fifteen patients underwent biopsy: MASH and fibrosis ≥F2 were found in 8 (53.3%), including 2 with cirrhosis.Conclusions: Sequential screening using Fib-4 and LS accurately identifies high-risk MASLD patients requiring hepatology referral. Severe obesity independently associates with LS ≥8 kPa even in low-risk Fib-4 individuals. Dual elastographic assessment may outperform Fibroscan® alone, reducing false negatives and improving advanced fibrosis detection in obese populations.

Background & Aim: Primary biliary cholangitis (PBC) is often associated with extrahepatic autoimmune (EADs) and/or cardiometabolic conditions (CMCs). We hypothesized that these comorbidities may display distinct clinical features compared with those with isolated PBC. This study assessed the prevalence of EADs and CMCs and explored their influence on the clinical presentation of PBC.Methods: This retrospective cohort study included PBC patients followed in 57 Italian centers enrolled in the Italian National PBC Registry (Study: PBC322).Collected data included demographics, baseline laboratory tests, liver stiffness measurement (LSM) and the presence of PBC-autoimmune hepatitis (AIH) variant. Information on the type and timing of EADs, CMCs (overweight/obesity, glucose metabolism disorders, hypertension, dyslipidemia) and cardiovascular diseases (CVD) -coronary artery disease, cerebrovascular disease and peripheral artery disease- was recorded. Within the CMCs, a subgroup with diabetes and/or metabolic syndrome (D/MS) was identified. Results: Of 3,142 registry patients 2,340 met inclusion criteria. Women accounted for 89%, median age at inclusion was 54.9±4.3 years, and median PBC duration was 4.9 years (IQR 1.5-10.7). The mean BMI was 24.9±4.3. A PBC-AIH variant was diagnosed in 7%, and 23% had cirrhosis at baseline. EADs were present in 27% of patients, mainly autoimmune thyroid diseases (11%), Sjogren's syndrome (7%), systemic sclerosis (4%), rheumatoid arthritis (2%), systemic lupus erythematosus (1%), vitiligo (1%) and other EADs (3%). CMCs were frequent: dyslipidemia 43%, arterial hypertension 37%, diabetes mellitus 9%, and obesity 10%. Cirrhosis and CVD were more common in patients with D/MS and those with EADs+D/MS (cirrhosis 30% and 25%; CVD 7% and 9%) compared with patients without comorbidities (cirrhosis 23%; CVD 3%) and those with EADs alone (cirrhosis 19%; CVD 4%) (p=0.021 for cirrhosis; p<0.001 for CVD). Similarly, LSM was higher in patients with D/MS and EADs+D/MS (7.1 kPa [4.8-11.1] and 6.4 kPa [4.9-9.1]) than in those with only EADs or no comorbidities (5.9 kPa [4.4-8] and 5.8 [4.5-8.4]) (p=0.005). The prevalence of PBC-AIH variant was greater in patients with EADs and EAD+D/MS (12% and 15%) than in those with only D/MS or no comorbidities (4% and 5%) (p<0.001). Conclusion: EADs and CMCs are common in PBC. CMCs - particularly diabetes and metabolic syndrome- are associated with more advanced liver disease and increased CVD risk, suggesting an interference with their occurrence. EADs are linked to a higher prevalence of the PBC–AIH variant. Ongoing analyses aim to further characterize the impact of these comorbidities on treatment response and survival.