Chaowapong Jarasvaraparn

The optimal induction regimen for pediatric liver transplantation (LT) in patients with Autoimmune Liver Disease (AILD) is not well-defined. This study compared outcomes between corticosteroids only, anti-thymocyte globulin (ATG), and IL-2 receptor antagonists (IL2RA; Basiliximab/Daclizumab). A retrospective review of 445 pediatric LT recipients with AILD (Autoimmune hepatitis, primary sclerosing cholangitis, or autoimmune sclerosing cholangitis) was conducted using the SPLIT database. Re-transplants were excluded. Primary outcomes included biopsy-confirmed rejection, culture-proven infection, graft loss, and mortality. Baseline demographics were comparable across groups. At 30 days post-LT, the IL2RA group demonstrated a significantly lower rate of biopsy-confirmed rejection (11.2%) compared to corticosteroids only (20.9%) and ATG (28%; p =0.05). Conversely, the ATG group experienced a significantly higher incidence of culture-proven infections between days 30–90 (42.9%) compared to corticosteroids only (10.2%) and IL2RA (17.9%; p =0.03). In multivariable-adjusted models, ATG induction was associated with a 10-fold higher risk of sub-acute culture-proven infection at 30–90 days (aOR=10.0, 95%CI: 1.4–71.8, p =0.02) compared to corticosteroids alone. However, neither ATG (aOR=0.47) nor IL-2RA (aOR=0.63) significantly altered the odds of early acute rejection at 0–30 days ( p >0.30). No significant differences were observed in graft loss, mortality, disease recurrence, or post-transplant lymphoproliferative disorder up to five years post-transplant. In pediatric AILD, induction with IL2RA significantly reduces early acute rejection without increasing infection risks or compromising long-term graft and patient survival.

Background/Objectives: Interpretation of NOTCH2 variants of uncertain significance (VUSs) remains challenging in pediatric cholestasis and suspected Alagille syndrome (ALGS) due to incomplete penetrance, phenotypic variability, and extensive genetic variation. Although disease-specific variant classification criteria have identified pathogenic hotspots within epidermal growth factor (EGF)-like repeats 8–12 and ankyrin repeat domains 3–6, characterizing these VUSs requires a robust framework. Methods: We reviewed aggregate deidentified data from 519 multigene cholestasis panel entries and evaluated genotype–phenotype data from a consortium cohort of 7 pediatric patients with heterozygous NOTCH2 VUSs using a clinical–genomic prioritization framework informed by disease-specific ACMG criteria and domain location. Results: Across the 519 entries, 365 unique NOTCH2 VUSs were identified, none of which overlapped with 69 previously reported ALGS-associated variants or localized to established hotspots, with over 60% occurring outside recognized functional domains. Among the 7 consortium cases, one patient carrying a cysteine-altering variant (p.Cys593Arg) in EGF-like domain 15 demonstrated a strong ALGS-compatible phenotype, while alternative diagnoses in other cases included trisomy 21 and congenital hepatic fibrosis with polycystic kidney disease. Conclusions: Among 365 unique NOTCH2 VUSs identified through pediatric cholestasis panel testing, none overlapped with previously reported ALGS-associated variants or localized to established pathogenic hotspots. However, a cysteine-altering variant outside canonical hotspots occurred in a patient with a strong ALGS-compatible phenotype, highlighting the importance of integrating variant characteristics, domain location, detailed phenotyping, and alternative diagnoses when prioritizing NOTCH2 VUSs for further evaluation.

Progressive familial intrahepatic cholestasis (PFIC) is classically caused by biallelic pathogenic variants, yet monoallelic variants of uncertain significance (VUS) in PFIC‐associated genes are increasingly identified in children with cholestasis, creating diagnostic uncertainty. We conducted a multicenter cohort study of children with liver disease and/or cholestasis harboring monoallelic VUS in ATP8B1 , ABCB11 , ABCB4 , TJP2 , or NR1H4 . Clinical and longitudinal data were analyzed, and variant frequencies were compared with population data from gnomAD. Twenty‐six children with 37 monoallelic PFIC‐gene VUS met inclusion criteria, and multigenic variant burden was common (73.1%). PFIC‐like biochemical patterns were observed in 42.3% but were frequently transient, and no patient met criteria for monogenic PFIC on longitudinal follow‐up. Severe liver outcomes, including transplantation in two patients, occurred in a subset of patients with ABCB4 and/or ATP8B1 VUS and multigenic burden, along with competing clinical factors. Among 22 variants with population data, 11 (50%) demonstrated significant enrichment after multiple‐testing correction, most commonly involving ABCB4 . These findings suggest that monoallelic PFIC‐associated variants currently classified as VUS are unlikely to represent monogenic disease drivers in isolation and may instead contribute within multigenic or susceptibility‐based contexts. Population‐level enrichment, particularly involving ABCB4 , further supports careful phenotype‐anchored, longitudinal interpretation in pediatric liver disease.

Hereditary fructose intolerance (HFI) typically presents in infancy with acute metabolic crisis upon the introduction of fructose. We report a case of a 13‐year‐old female with chronic abdominal pain, short stature, and persistent mild transaminitis. Despite a late presentation, hepatic steatosis was identified on ultrasound and biopsy. Genetic testing confirmed a homozygous pathogenic ALDOB variant. This case illustrates that self‐imposed dietary avoidance can mask classic HFI symptoms, leading to a delayed diagnosis of “lean” hepatic steatosis in adolescence.

Purpose of Review: This manuscript reviews the clinical spectrum and management of Fontan-associated liver disease (FALD) and protein-losing enteropathy (PLE), examining how chronic venous hypertension leads to multisystem injury. Recent Findings: Liver fibrosis is now recognized as an early and nearly universal complication after the Fontan procedure, with cirrhosis affecting approximately 43% of patients by 30 years post-operation. Although post-2001 survival exceeds 90%, standard biomarkers and imaging frequently underestimate disease severity, as liver stiffness measurements are confounded by hepatic congestion. Liver biopsy remains the gold standard for staging. Summary: FALD is an inevitable consequence of Fontan physiology, characterized by sinusoidal congestion and progressive fibrosis, while PLE results from multifactorial gastrointestinal protein loss. The key clinical implication is the importance of a multidisciplinary approach, particularly when considering transition from isolated heart transplantation to combined heart–liver transplantation in advanced disease. Future research should prioritize standardized staging systems and targeted therapies to reduce lymphatic dysfunction and fibrosis progression.

Objectives: Liver biopsy remains the gold standard to evaluate fibrosis. Vibration‐controlled transient elastography (VCTE) utilizing FibroScan allows for non‐invasive measurement of liver stiffness in liver transplant (LT) recipients. This study investigated the utilization of FibroScan in pediatric liver transplant recipients. Methods: In a retrospective single‐center analysis of children with LT who underwent at least one FibroScan, we investigated the correlation of biomarkers such as controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) from FibroScan with the severity of steatosis and fibrosis on liver biopsy. Advanced fibrosis (AF) was defined as bridging fibrosis and/or cirrhosis (fibrosis score 3–4) on liver biopsy. Results: A total of 166 FibroScans from 74 children with LT (10 split and 64 whole liver) were included. Forty‐seven children underwent liver biopsies. LSM was significantly correlated with AF ( r = 0.63, p = 0.001). LSM greater than 7.9 kPa predicted AF with AUC 0.96% and 99% sensitivity, 84% specificity ( p = 0.001). The 11 children with CAP ≥ 225 dB/m did not have any biopsy evidence of steatosis. Split liver recipients had significantly higher LSM than whole liver recipients (10.4 vs. 5.9 kPa, p = 0.05). Conclusions: VCTE is a practical tool to assess graft fibrosis in children with LT. Split livers have higher LSM measurement, which does not correlate with AF on biopsy. We speculate that VCTE can be useful for graft fibrosis surveillance in children with LT.

Background: Despite major advances in surgical and medical management, only one-third of pediatric liver transplant (LT) recipients remain morbidity-free at 10 years. The Society of Pediatric Liver Transplantation (SPLIT) published a research agenda over 10 years ago, and much progress has been made since then. An updated consensus-driven SPLIT research agenda could guide future research and funding priorities. We aimed to identify and prioritize key research needs across the continuum of pediatric LT care using a modified Delphi consensus approach. Methods: We conducted a three-round modified Delphi process among SPLIT members. In round 1, participants submitted open-ended research priorities. In round 2, the Steering Committee synthesized these into 156 unique statements for rating. The third and final round included revision and rerating of 42 statements. Consensus was defined as a median importance rating ≥7 on a 9-point Likert scale. Results: Sixty-nine multidisciplinary experts participated in round 1, with Export