Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common reason for elevated liver enzymes in children in Europe, affecting more than 5% of all children. Since the last iteration of this position paper, there have been substantial advances in our understanding of the disease. After a detailed literature review and thorough discussion, we established consensus recommendations for the diagnosis and assessment of MASLD in children. Alanine aminotransferase (ALT) >= 30 IU/L is a suitable screening test for MASLD in children over 10 years of age with obesity (body mass index z-score >=+2), or in children of any age with additional risk factors. All patients with suspected MASLD should be assessed for alternative or concomitant diagnoses, as well as comorbidities. Patients who are not overweight, under 8 years old, or have any other red flags should be promptly referred for specialist assessment. Liver biopsy remains the gold standard for diagnosis and staging of MASLD, but should be reserved for diagnostic uncertainty, to guide treatment decisions, and risk stratification (e.g., prior to transition to adult care). While there is emerging data for non-invasive tests (e.g., transient elastography), it is unclear how to routinely implement these investigations in clinical practice. Combined changes of >= 20% in both ALT and gamma-glutamyl transferase may represent a useful non-invasive tool for monitoring disease severity over time. Most patients are appropriately investigated and managed by non-specialists where the focus is on holistic management of obesity and its complications. Future research should focus on how to use non-invasive tests to risk-stratify children, in particular, how to identify those with advanced fibrosis.

BACKGROUND AND AIMS:Primary sclerosing cholangitis recurrence (rPSC) after liver transplantation (LT) is common; however, the factors contributing to rPSC are poorly understood. This study aimed to identify the risk factors for rPSC after LT and determine whether donor type affects rPSC. METHODS:A multicenter retrospective cohort analysis was conducted on 174 patients with PSC who underwent LT between January 2000 and January 2024. Multivariable Cox models were used to evaluate risk factors for rPSC. The rPSC risk for living donor liver transplantation (LDLT) and deceased donor liver transplantation (DDLT) recipients was compared using Kaplan-Meier survival curves and log-rank tests. RESULTS:Of the 174 recipients, 144 (83%) underwent LDLT and 30 (17%) underwent DDLT. Sixty-four (37%) had inflammatory bowel disease (IBD) prior to LT. Thirty-three patients (19%) had rPSC after LT. The median time to rPSC was 28 months (IQR 6-252). Patients with rPSC were younger at the time of PSC diagnosis, and had a higher prevalence of biliary complications after LT and concomitant IBD than those without recurrence. Multivariable Cox regression identified LDLT (HR 3.92, 95% CI 1.06-14.51, p = 0.041), biliary complications (HR 2.18, 95% CI 1.05-4.54, p = 0.037), IBD (HR 2.42, 95% CI 1.20-4.89, p = 0.013), and acute cellular rejection (HR 2.43, 95% CI 1.08-5.48, p = 0.032) as independent risk factors for rPSC. CONCLUSIONS:This multicenter study identified LDLT, acute cellular rejection, IBD, and biliary complications as independent risk factors for rPSC. These findings underscore the need for individualized post-transplant surveillance and provide important considerations for graft selection and perioperative management in patients with PSC, particularly in settings where LDLT is predominant.

Background: Autoimmune hepatitis (AIH) is an important indication for liver transplantation (LT), but recurrence affects over 30% of recipients, threatening long-term survival. Current strategies to prevent recurrence and progressive graft fibrosis remain suboptimal, with limited evidence to guide selection of immunosuppressive regimens. We aimed to develop a dynamic, individualized, artificial intelligence–powered model for post-transplant recurrent AIH. Methods: We conducted a multicenter, retrospective cohort study of 706 patients who underwent LT for AIH between January 1987 and June 2020 at 33 centers in North America, South America, Europe, and Asia. We trained 4 predictive machine learning models—Logistic Regression, Random Forest, XGBoost, and Gradient Boost—to predict recurrent AIH (rAIH) using 62 clinical and laboratory variables, including demographic, biochemical features, and immunosuppressive drugs up to 1-year post-transplant. Feature importance was assessed using SHapley Additive exPlanations (SHAP) to enable interpretability at both individual and population levels. Results: AIH recurred in 16.5% of patients after LT. SHAP analysis identified younger age at LT, higher necroinflammatory activity in the explanted liver, and elevated MELD score at LT as key predictors of rAIH in the overall population. Tacrolimus-based therapy was associated with a lower risk of recurrence, while cyclosporine use conferred a higher risk. The addition of long-term prednisone to a regimen of tacrolimus and mycophenolate mofetil did not provide additional protective effect against rAIH. Conclusions: Our AI-powered clinical decision model provides personalized prediction of post-transplant rAIH. While it offers insight into modifiable and non-modifiable predictors, prospective validation is required before informing immunosuppressive decisions.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common reason for elevated liver enzymes in children in Europe, affecting more than 5% of all children. Since the last iteration of this position paper, there have been substantial advances in our understanding of the disease. After a detailed literature review and thorough discussion, we established consensus recommendations for the diagnosis and assessment of MASLD in children. Alanine aminotransferase (ALT) ≥ 30 IU/L is a suitable screening test for MASLD in children over 10 years of age with obesity (body mass index z-score ≥+2), or in children of any age with additional risk factors. All patients with suspected MASLD should be assessed for alternative or concomitant diagnoses, as well as comorbidities. Patients who are not overweight, under 8 years old, or have any other red flags should be promptly referred for specialist assessment. Liver biopsy remains the gold standard for diagnosis and staging of MASLD, but should be reserved for diagnostic uncertainty, to guide treatment decisions, and risk stratification (e.g., prior to transition to adult care). While there is emerging data for non-invasive tests (e.g., transient elastography), it is unclear how to routinely implement these investigations in clinical practice. Combined changes of ≥20% in both ALT and gamma-glutamyl transferase may represent a useful non-invasive tool for monitoring disease severity over time. Most patients are appropriately investigated and managed by non-specialists where the focus is on holistic management of obesity and its complications. Future research should focus on how to use non-invasive tests to risk-stratify children, in particular, how to identify those with advanced fibrosis.

BACKGROUND AND AIMS:Pathogenic variants in neuroblastoma amplified sequence (NBAS) gene causes infantile liver failure type 2 (IFLS2; MIM 616483), characterised by recurrent episodes of liver failure triggered by febrile infections. The underlying pathophysiological mechanisms remain incompletely understood. With this work we try to shed light on the pathomechanism and propose a potential therapeutic option. METHODS:For in vitro analyses, human skin fibroblasts were obtained from three individuals with ILFS2 and one healthy control. Cells were cultivated at 37°C or 40°C. Western blots were performed to assess NBAS protein and its interaction partners. Furthermore, immunofluorescence and electron microscopy were used to examine morphological changes associated with endoplasmic reticulum (ER) stress. Apoptosis was measured using flow cytometry. The effects of N-acetylcysteine (NAC) treatment were analysed not only in cultured fibroblasts but also in vivo retrospectively in 16 affected individuals. RESULTS:We demonstrate that elevated temperature induces ER stress in fibroblasts from individuals with NBAS variants, leading to increased reactive oxygen species (ROS) production and apoptosis. Treatment with the antioxidant NAC, an established therapeutic in acetaminophen-induced liver failure, effectively mitigated oxidative stress and reduced apoptosis in vitro. In a retrospective clinical analysis, there was a trend that NAC treatment was associated with reduced severity of hepatic crises, suggesting a potential therapeutic benefit. CONCLUSIONS:Our findings link fever-induced ER stress, ROS accumulation, and apoptosis to the pathogenesis of liver failure in NBAS deficiency. NAC attenuates these cellular stress responses and may represent a promising supportive treatment option in NBAS-associated liver failure.

Introduction: Celiac disease (CD)-related antibody positivity in children with type 1 diabetes (T1D) may fluctuate and become negative spontaneously. There are uncertainties about the optimal tissue transglutaminase IgA (tTG-IgA) titre and timing of endoscopy in the diagnosis of CD, and this study aimed to contribute to the debate on the tTG-IgA threshold titre for endoscopy decisions in children with T1D. Methods: The data of 991 children with T1D who had undergone serologic evaluation for CD were analysed retrospectively. The tTG-IgA positivity rate and the upper limit of normal (ULN) tTG-IgA positivity were assessed. Participants were grouped according to the frequency, course, and test results of tTG-IgA tests. Those with and without histopathologic diagnosis of CD by endoscopic biopsy were compared in terms of tTG-IgA screening time and tTG-IgA predictive values. Results: In 10.2% (n:101) of all cases, tTG-IgA antibody was positive and endoscopic biopsy was performed in 68.3% (n:69) of these cases. Of all cases, 4.3% (n:43) were diagnosed with CD by endoscopic biopsy. A tTG-IgA titre of 7xULN and above was found to be the best predictive value for the diagnosis of CD with 79.1% sensitivity, 80.8% specificity 87.2% positive predictive value, and 70% negative predictive value. Conclusions: Approximately 10% of antibody positive cases showed fluctuating and low-titre positivity, and no CD was detected by endoscopic biopsy in the group with fluctuating antibody course. The results of our study suggest that endoscopy in children with tTG-IgA levels 7xULN or above may prevent both false-positive results and missed cases.

ABSTRACT Background and Aim Alagille syndrome (ALGS) is a rare disorder characterised by cholestasis and extrahepatic manifestations. Given the current era of ileal bile acid transporter (IBAT) inhibitor therapies that reduce serum bile acid (SBA) levels, we evaluated whether SBA predicts liver disease outcomes in ALGS. Methods Patients were ascertained from the G lobal AL agille A lliance (GALA) cohort. A prognostic threshold of SBA 102 μmol/L was assessed as a time‐dependent covariate in Cox regression analyses for native liver survival (NLS) and event‐free survival (EFS), while adjusting for total bilirubin (TB) levels. Results 570 GALA patients were included (348 [61%] male). There was a moderate positive correlation between SBA and TB (Pearson correlation = 0.47, p < 0.001). SBA below 102 μmol/L was a significant predictor of outcomes (NLS: HR = 3.78, 95% CI 2.39–5.99, p < 0.001; EFS: HR = 3.44, 95% CI 2.35–5.04, p < 0.001). SBA remained a significant predictor for improved EFS after adjusting for TB clearance at 1 year (TB < 2 mg/dL; HR = 2.00, 95% CI 1.10–3.65, p = 0.02). Median SBA in the first year of life above 102 μmol/L, predicted lower NLS (67.2% vs. 83.5% at 7 years p = 0.05) and EFS (63.4% vs. 80.9% at 7 years, p = 0.02). Conclusion Lower SBA in children with ALGS liver disease predicts improved NLS and EFS. SBA is also associated with NLS in children with ALGS who clear their bilirubin, that is, those with anicteric cholestasis. Although the patients studied here did not receive IBAT inhibition, these data suggest that lowering SBA may improve important clinical outcomes.

BACKGROUND & AIMS:Alagille syndrome (ALGS) is a rare, autosomal dominant disorder with high phenotypic heterogeneity. Disease-causing variants are primarily identified in Jagged1 (JAG1), with fewer reported in NOTCH2. JAG1 variants cause disease through a mechanism of haploinsufficiency, but the mechanism for NOTCH2 variants is not completely understood, making classification of variants more challenging. Using a large, international patient cohort acquired through the Global ALagille Alliance (GALA) study, we sought to improve classification of NOTCH2 variants and study phenotypic differences between NOTCH2- and JAG1-related disease. METHODS:Clinical and molecular data from 952 individuals with ALGS in GALA were analysed and disease features compared between those with JAG1 (n = 902) and NOTCH2 (n = 34) variants. Previously reported and newly identified NOTCH2 variants were reinterpreted based on disease-specific modifications to the American College of Medical Genetics and Genomics (ACMG) guidelines. The Kaplan-Meier method was utilised to assess native liver survival (NLS) and overall survival (OS) and gene comparisons were made with the log-rank test. RESULTS:Thirty NOTCH2 variants, including 18 novel variants, were identified and classified in our GALA cohort. Phenotypic analyses revealed a significantly lower incidence of characteristic facies, posterior embryotoxon, cardiac involvement and butterfly vertebrae in individuals with NOTCH2 variants compared to those with JAG1 variants (p < 0.001). No differences were identified in NLS or OS. Review of 61 previously reported NOTCH2 variants resulted in the re-classification of 19 likely pathogenic or pathogenic to VOUS (31.1%) with less than half retaining their originally published classification (34.4%; n = 21). CONCLUSIONS:We report on a large global study on NOTCH2 genetics and phenotype, which increases the number of reported NOTCH2 variants by 30%. All variants were reclassified using current guidelines, and comparison of the JAG1 and NOTCH2 cohorts demonstrates clear phenotypic divergence between these groups. These data suggest that reliance on classical clinical phenotyping may miss patients with NOTCH2-related disease and supports an inclusive approach to genetic testing.

This multicenter retrospective study analyzed 336 patients (236 adults, 100 children) who underwent liver transplantation (LT) for acute liver failure (ALF) between 2002 and 2019 across 14 centers in Türkiye. The aim was to evaluate pretransplant factors influencing short-term posttransplant survival. Median MELD and PELD scores were 31 and 30, respectively. The most common ALF etiologies were viral, indeterminate, and drug-induced causes. Living donor liver transplantation (LDLT) was more common in children (86.0%) than adults (57.2%). Mean posttransplant survival was 166±9 months in children and 117±6 months in adults. In adults, LDLT significantly improved survival compared to deceased donor LT (DDLT), with survival of 135 vs. 89 months (p=0.0012). Although pediatric LDLT recipients had longer mean survival than DDLT recipients (167 vs. 132 months), this difference was not statistically significant (p=0.5959). Three-month mortality was associated with low albumin and grade 4 hepatic encephalopathy (HE) in children. In adults, independent predictors of early mortality included DDLT, serum sodium >140 mEq/L, MELD >35, pH <7.3, and grade 4 HE. Our data suggest that LDLT may offer a survival advantage, particularly in adults with ALF. Identifying pretransplant risk factors is essential for improving early outcomes and guiding clinical decision-making.

Background & Aims:A significant proportion of patients with variant syndromes (VSs), namely autoimmune hepatitis/primary biliary cholangitis or autoimmune hepatitis/primary sclerosing cholangitis, require liver transplantation (LT) despite treatment. The frequency of disease recurrence and the effect on graft survival are yet to be clarified. The aim of this international, multicentric, retrospective study is to evaluate the risk factors associated with recurrence and the impact of the disease recurrence after LT on graft and patient survival. Methods:We evaluated 166 patients undergoing LT for VS in 33 centers in North America, South America, Europe, and Asia. Clinical data before and after LT, biochemical data within the first 12 months after LT, and immunosuppression after LT were analyzed to identify patients with a higher risk of recurrence of autoimmune disease based on a histological and radiological diagnosis. Cumulative probabilities of graft and overall survival after LT were calculated using a semi-Markov model. Results:The autoimmune pattern of recurrence resembled the original VS in 19 cases (61%). Recurrence of autoimmune liver disease (rALD) after LT was observed in 23% and 33% of patients after 5 and 10 years, respectively. Increased alkaline phosphatase (hazard ratio [HR] 1.60, 95% confidence interval [CI] 1.13-2.25, p <0.01) and alanine aminotransferase (HR 1.25, 95% CI 1.01-1.53, p = 0.03) at 12 months after LT and acute rejection (HR 3.58, 95% CI 1.60-7.73, p <0.01) were associated with a higher risk of VS recurrence, whereas the use of predniso(lo)ne was associated with a reduced risk (HR 0.30, 95% CI 0.14-0.64, p <0.01). After adjusting for alanine aminotransferase and alkaline phosphatase at 12 months, the use of predniso(lo)ne was found to be independently and negatively associated with recurrent disease. The rALD was found to be significantly associated with graft loss and patient survival in the multivariate Cox regression analysis with a time-dependent covariate. The 5- and 10-year probabilities of graft survival were 68% and 41% in patients with recurrent VS compared with 83% and 60% in patients without recurrent disease, respectively (p = 0.01). The overall survival was significantly reduced in patients with recurrent disease (p = 0.01), with event probability at 5 and 10 years of 75% and 49% vs. 84% and 60% in patients without recurrence, respectively. Conclusions:rALD after LT is frequent and is associated with elevation in liver enzymes within the first year after LT and rejection episodes. According to our data, VS recurrence appears to be associated with poorer graft and patient survival. Further studies are needed to explore strategies that can prevent VS recurrence or mitigate its potential impact. Impact and implications:This study investigated the recurrence of autoimmune liver diseases (rALD) in patients transplanted for variant syndromes (VSs) and its effect on graft and patient survival. The findings reveal a significant association between rALD and poorer graft and overall survival, highlighting the need for preventive strategies. This research is crucial for transplant physicians and healthcare providers, as it underscores the impact of early liver enzyme monitoring and tailored immunosuppressive therapy on long-term outcomes. These insights can inform more effective post-LT management protocols, potentially improving patient prognosis.

BACKGROUND AND AIMS:Since described in 2015, NBAS-associated disease has emerged as an important cause of acute liver failure (ALF) in children. We analysed the variable expression, genotype-phenotype association, outcome and prognostic factors of the hepatic involvement. METHODS:Individuals with biallelic pathogenic NBAS variants were recruited within an international observational study, including new and previously published patients. RESULTS:We studied 230 individuals, including 13 previously unreported patients. The liver was the most frequently affected organ (63.4%), with 41.3% experiencing at least one ALF. The median age at onset was 0.9 years, the median age at last ALF 5 years, the latest ALF occurred at 24 years. Liver crises were triggered by febrile infections and presented with highly increased hepatic transaminases. Liver involvement varied significantly between the subgroups: 91.7% of patients with infantile liver failure syndrome type 2 and 88.9% of patients from the combined subgroup (variants affecting β-propeller domain) presented with ALF, whereas SOPH (stature, optic atrophy, Pelger-Huët anomaly) patients mostly had either no liver involvement (66.4%) or persistently elevated transaminases without ALF (28%). The rate of native liver survival was 83.9%; 16 individuals underwent liver transplantation and 24 died. CONCLUSION:Liver abnormalities are common and the leading cause of death in NBAS-associated disease. There is a clear genotype-phenotype association regarding the hepatic involvement. Liver crises occur primarily during infancy; however, early medical attention in case of febrile infections is necessary at all ages. Liver transplantation prevents ALF, but its risks must be weighed against the frequency and severity of liver crises decreasing with age.