ABSTRACTBackground and AimsThe phase II REPLACEMENT study showed promising clinical benefit from atezolizumab plus bevacizumab in transcatheter arterial chemoembolization (TACE)–naïve patients with intermediate‐stage hepatocellular carcinoma (HCC) beyond up‐to‐7 criteria, meeting its primary endpoint of progression‐free survival (PFS). Here, we report the final overall survival (OS) analysis.MethodsEnrolled patients were naïve to TACE with unresectable intermediate‐stage HCC beyond up‐to‐7 criteria, had Child‐Pugh A, Eastern Cooperative Oncology Group performance status 0/1 and received no previous systemic therapy. Atezolizumab 1200 mg and bevacizumab 15 mg/kg were administered every 3 weeks. The primary endpoint was the 6‐month PFS rate by modified Response Evaluation Criteria in Solid Tumours for HCC (mRECIST); secondary endpoints included OS, PFS by RECIST version 1.1, objective response rate (ORR) and safety.ResultsOverall, 74 patients were enrolled between December 2020 and September 2021. At the clinical cut‐off date (March 31, 2024), median follow‐up was 33.6 months. Median PFS by mRECIST was 9.1 months (95% CI 7.1–10.2). Median OS was 33.8 months (95% CI 22.6–not estimable). ORR was 40.5% (95% CI 29.3–52.6), with 12.2% of patients having a complete response. Overall, 82.4% of patients received subsequent therapy. All‐cause adverse events (AEs) were observed in 98.6% of patients, most commonly hypertension (71.6%) and proteinuria (54.1%). Grade 3/4 AEs occurred in 43.2% of patients; no Grade 5 AEs were reported.ConclusionsThese results show that atezolizumab plus bevacizumab can be an alternative treatment option for patients with intermediate‐stage HCC beyond up‐to‐7 criteria who are deemed unsuitable for TACE.Trial RegistrationjRCTs071200051

ABSTRACTThe relationship between frailty and gut microbiota has not been previously addressed in patients with cirrhosis. We studied by metagenomic shotgun sequencing the faecal microbiota composition associated with frailty in 29 patients with cirrhosis from a previous study (Román, Hepatol Commun 2024). Frail and prefrail patients were randomised to a multifactorial intervention (home exercise, branched‐chain amino acids and a multistrain probiotic) or control for 12 months. We observed a positive correlation between the abundance of Rothia dentocariosa and the Liver frailty index (LFI), and between Bacteroides faecis and gait speed. After the multifactorial intervention, LFI improved and the main changes in the microbiota composition were a decrease in the abundance of Akkermansia muciniphila, and an increase in Streptococcus thermophilus, Lactobacillus acidophilus and several species of Bifidobacterium. We conclude that frailty in patients with cirrhosis was associated with a distinct microbiome signature. After a long‐term multifactorial intervention, frailty improved in parallel with changes in microbiome composition.Trial Registration:ClinicalTrials.gov identifier: NCT04243148.

ABSTRACTBackground and AimsRecurrent acute liver failure (RALF) in children is defined as two or more episodes of acute liver failure with complete recovery in between. Several genetic mutations are associated with this condition, including NBAS, RINT1, LARS1 and SCYL1. We have reported liver transplant and mortality rates to help providers make informed management decisions.MethodsWe conducted a systematic review and one‐stage individual participant analysis using EMBASE, MEDLINE and Web of Science for English‐language studies of RALF occurring in children with NBAS, RINT1, LARS1 or SCYL1 mutations published on or prior to May 14th, 2025.ResultsOur search query identified 62 articles, including 38 (66%) case reports, 13 (22%) case series and 6 (11%) cohort studies. A total of 168 (males, 40%) patients were identified, with first presentation at a median age of 9 months (range 1 week–18 years) and preceded by fever in 110/114 (98%) children. The last episode was documented at a median of 4 years (2 months to 21 years). Patients had a median of 4 (range 2–30) episodes, with only 8 (5%) patients experiencing events after age 10 years. Commonest mutated genes identified were NBAS (66%, n = 111) and LARS1 (18.4%, n = 31). Liver transplant was undertaken in 18 (11%) patients, with no recurrences reported post‐transplant. Death was reported in 29 (17.3%) patients.ConclusionsMost patients with RALF present in the first year of life and have a self‐limiting course. Episodes of acute liver failure are often associated with febrile illness. Liver transplantation for RALF remains controversial and may be less appealing in etiologies that tend to resolve with age. We recommend whole‐exome sequencing with a targeted search for NBAS, SCYL1, RINT1 and LARS1 for patients presenting with unexplained acute liver failure in the setting of a febrile illness.

ABSTRACTSemaglutide has recently received conditional accelerated approval in the US for treatment of metabolic dysfunction‐associated steatohepatitis (MASH) with significant or advanced liver fibrosis (stage F2/F3). Phase 2 and 3 clinical trials show that subcutaneous semaglutide 2.4 mg/week leads to significant improvements in hepatic steatosis, disease activity, resolution of MASH and reduction in liver fibrosis. These benefits parallel weight loss and are accompanied by improved metabolic outcomes, including better glucose control and lipid profiles, as well as consistent benefits for cardiovascular and renal health. The treatment's safety profile is manageable, with gastrointestinal issues being the most frequent side effects, and no new safety concerns have been identified. Data on long‐term tolerability, treatment retention and clinical events are now awaited in people with MASH fibrosis. The evidence regarding semaglutide's ability to directly target the liver and improve liver damage in cirrhosis, and its impact on muscle mass in at‐risk populations, remains limited. Thus, in patients with advanced disease, it should be viewed primarily as a therapy that modifies metabolic disease. Practically, semaglutide is most suitable as a first‐line treatment to prevent liver complications for people with MASH and stage F2/F3 fibrosis with severe metabolic dysfunction, obesity, or type 2 diabetes who could benefit from both liver and cardiovascular‐renal improvements. Treatment should be tailoured to each individual, with ongoing monitoring of body weight, serum aminotransferase levels and direct measurement of liver fat and stiffness to guide therapy.

ABSTRACTBackground and AimsPrimary sclerosing cholangitis (PSC) is a progressive, refractory liver disease often requiring liver transplantation (LT). The association between the disease onset and specific human leukocyte antigen (HLA) typing has been noted, but its relevance in the Japanese population is unknown.MethodsThe HLA 5 locus (HLA‐A, B, C, DRB1 and DQB1) 4‐digit genotyping results of 31 patients with progressive PSC who underwent LT at our institution were compared to those of 873 healthy Japanese controls.ResultsHLA‐B*07:02 (p‐corrected [pc] = 1.9 × 10−2), HLA‐C*07:02 (pc = 3.9 × 10−5), HLA‐DQB1*05:01 (pc = 3.7 × 10−2), and HLA‐DRB1*01:01 (pc = 1.7 × 10−2) were identified as the susceptibility alleles for PSC. This correlation was stronger in patients with PSC complicated by ulcerative colitis than in those with PSC alone. Furthermore, analyses of the amino acid sequences of each HLA protein revealed that 15 amino acid residues of HLA‐C were significantly associated with disease susceptibility (pc = 1.5 × 10−4‐4.5 × 10−4).ConclusionsHLA‐C*07:02 is vulnerable to PSC aggravation in the Japanese population.

ABSTRACTBackground and AimsHepatic immune cell analysis is critical for understanding chronic inflammatory liver diseases, such as primary sclerosing cholangitis (PSC) and steatotic liver disease. However, liver immunoprofiling is limited due to reliance on end‐stage disease liver explants. Fine needle aspiration (FNA) is a minimally invasive technique that can overcome these limitations. We evaluate the safety and efficacy of liver FNA to profile hepatic immune subsets in non‐infectious liver conditions.MethodsFlow cytometry and single‐cell RNA sequencing (scRNA‐seq) were used to compare the hepatic immune cell composition and gene expression to that of matched peripheral blood mononuclear cells (PBMCs).ResultsWe obtained liver FNAs from 38 patients. The median pain score was 0. No serious adverse effects were reported. Flow cytometry demonstrated enrichment of CD69+ T and natural killer (NK) cells in the liver (all Padj < 0.05). ScRNA‐seq of 38 012 hepatic immune cells and 78 751 PBMCs in a patient subset showed specific enrichment of CXCR6+ NK, CD8+ central memory T, and mucosal‐associated invariant T (MAIT) cells in the liver, and relatively lower CD4+ regulatory T cell (Treg) abundance (all Padj < 0.05). Gene expression and cell–cell interaction analyses revealed increases in cytokine production, signalling, and responsiveness in hepatic immune cells compared to PBMCs.ConclusionsFNA sampling is a safe approach for investigating the inflammatory landscape of PSC and other liver diseases. Single‐cell profiling reveals that FNAs capture tissue‐specific immune cell types and gene expression differences, suggesting this sampling method may provide a basis for future experimental medicine analyses.

ABSTRACTBackgroundAlcohol‐associated liver disease (ALD) is a leading cause of liver‐related morbidity and mortality, yet effective therapeutic options remain limited. Preclinical data suggest that modulation of the hepatic endocannabinoid system, particularly via cannabidiol (CBD), may reduce alcohol‐induced liver injury. Due to CBD's limited clinical use, we sought to evaluate the association between cannabis use and ALD risk among patients with alcohol use disorder (AUD).MethodsUsing the TriNetX US Collaborative Network, we identified adult patients with AUD between 2010 and 2022. Three cohorts were constructed: cannabis use disorder (CUD), cannabis users without cannabis abuse or dependence (CU) and non‐cannabis users (non‐CU). Outcomes included ALD, hepatic decompensation and composite all‐cause mortality over 3 years. Incidence and hazard ratios were calculated using Kaplan–Meier analysis and Cox regression.ResultsAfter matching, 33 114 patients were included in each of the CUD and non‐CU groups. Compared to non‐CU, CUD was associated with a lower risk of ALD (HR 0.60, 95% CI 0.53–0.67; p < 0.001), hepatic decompensation (HR 0.83, 95% CI 0.73–0.95; p =0.005) and all‐cause mortality (HR 0.86, 95% CI 0.80–0.94; p < 0.001) among individuals with AUD. Although CU was associated with lower risks of ALD, its risks of hepatic decompensation and all‐cause mortality were similar to those of the non‐CU cohort with AUD.ConclusionIn this propensity‐matched cohort study of patients with AUD, cannabis use was associated with a reduced risk of ALD, with the greatest risk reduction seen in patients with CUD compared to CU and non‐CU. Our findings suggest that modulation of cannabinoid receptors may offer a new target for the development of pharmacological therapies for ALD.

ABSTRACTBackground and AimsNeutrophil myeloperoxidase is involved in different inflammatory diseases, including metabolic dysfunction‐associated steatohepatitis (MASH). Mitiperstat is a highly potent myeloperoxidase inhibitor. This phase 2a clinical trial evaluated the efficacy, safety, pharmacokinetics, and pharmacodynamics of mitiperstat in patients with non‐cirrhotic MASH.MethodsThe study enrolled 112 adult participants with histological MASH F1–3 fibrosis and increased alanine aminotransferase (ALT) levels. Participants were randomised 1:1 to once‐daily mitiperstat 5 mg or placebo. Primary and secondary endpoints were absolute and placebo‐adjusted changes from baseline to week 12 in ALT and N‐terminal type‐III collagen propeptide (Pro‐C3) levels. Exploratory endpoints included other MASH‐related biomarkers.ResultsAt week 12, there were no significant changes versus placebo for ALT (+7.5%, p = 0.893) and Pro‐C3 (−0.9%, p = 0.396), or any other MASH‐related biomarkers. Mitiperstat was safe and well tolerated.ConclusionThis study does not provide proof of concept that mitiperstat 5 mg exerts an anti‐inflammatory/anti‐fibrotic effect in MASH.Trial RegistrationClincalTrials.gov identifier: NCT05638737

ABSTRACTBackgroundBulevirtide (BLV) is the only approved therapy for chronic hepatitis D (CHD) and compensated liver disease. Daily subcutaneous injection and the need for refrigeration may pose challenges, especially in patients with limited language proficiency.AimsAssessment of patient‐reported BLV handling and satisfaction and association with virologic response.MethodsPatients receiving BLV were assessed using a structured questionnaire on injection preparation, administration, refrigeration, adverse effects, and language proficiency. Virologic response was defined as complete (≥ 2 log10 reduction from baseline or HDV RNA undetectable), intermediate (≥ 1 log10 but < 2 log10 reduction), non‐response (< 1 log10 reduction or increase), or breakthrough (> 1 log10 increase after ≥ 2 log10 reduction).ResultsA total of 115 patients from 30 countries were recruited at 12 German centres. German language skills were rated as good, sufficient, poor or absent in 58%, 25% and 17% of cases. Reported difficulties included injection preparation (17%), administration (25%) and refrigeration (27%). Patients without virologic response or with viral breakthrough reported difficulties with injection administration in 56% compared to 17% with intermediate or complete response (p = 0.0002), while no differences were observed regarding preparation or refrigeration. Injection site reactions occurred in 57% of patients. Overall, 82% were satisfied with the practical handling and 94% with the tolerability of BLV. Good language proficiency was associated with greater satisfaction with the practical handling (p = 0.0067), which in turn correlated with virologic response (p = 0.0001).ConclusionsBLV administration is generally well manageable. Limited language proficiency and injection difficulties may negatively affect patient satisfaction and potentially influence treatment outcomes.Trial RegistrationGerman Clinical Trials Registry (DRKS 00033153)