Catalina Jaramillo

Background and Aims: Management of portal hypertension in children, including primary prophylaxis of variceal bleeding, is controversial due to limited understanding of mortality risk after the first variceal hemorrhage (1VH). This international multicenter study was designed to advance understanding of outcomes after pediatric 1VH. Approach and Results: Center-specific characteristics and approaches to portal hypertension were determined at 44 international sites. K-means clustered the centers based upon volume and complexity of approaches [cluster 1 high (n=5), cluster 2 low (n=21), cluster 3 intermediate (n=18)]. Clinical features and outcomes after 1VH were available from 345 subjects. Factors associated with overall survival (OS) and survival with native liver (SNL) were estimated by Kaplan–Meier survival curves, log-rank tests, univariable and multivariable Cox regression models. OS and SNL were high in portal vein thrombosis and noncirrhotic diseases and significantly higher than biliary atresia and cirrhotic diseases ( p <.001). Diminished SNL was observed in decompensated disease [diuretics (ie, ascites) or hospitalization at 1VH], biliary atresia with poor bile flow, cirrhotic disease, after sclerotherapy, or no endoscopic intervention. Diminished OS was noted in those with cirrhosis or requiring sclerotherapy. Mortality at 6 weeks was determined and compared among clusters using the average treatment effect under the Rubin causal model. Overall, 6-week mortality was 4.1%, 1.4% in nonhospitalized subjects, and was significantly higher in cluster 2 versus 1 centers ( p =0.010). Conclusions: Immediate mortality after 1VH in children is low compared with adults. Outcomes after 1VH are diagnosis-specific and worse in decompensated disease and after sclerotherapy. Center-specific factors may influence immediate outcomes after 1VH.

Antibody‐mediated rejection (AMR) is an important but infrequent cause of pediatric liver allograft injury. There is a lack of standardized guidance, and treatment approaches vary across institutions. A writing group from the Society of Pediatric Liver Transplantation conducted a comprehensive review of the published literature and collected institutional guidance documents from pediatric transplant centers across the United States to synthesize current diagnostic and management approaches to AMR in pediatric liver transplant recipients. AMR is diagnosed by the presence of characteristic histologic injury, C4d deposition, circulating donor‐specific antibody (DSA), and exclusion of alternative causes of graft dysfunction, including T cell–mediated rejection. Management strategies focus on reducing circulating DSA through therapeutic plasma exchange and suppressing ongoing immune activation with corticosteroids and intravenous immunoglobulin. In severe or refractory cases, targeted therapies such as rituximab, bortezomib, and eculizumab may be considered. A stepwise diagnostic and management algorithm is presented. This resource outlines a practical approach to the diagnosis and management of AMR in pediatric liver transplantation, serving as a reference for busy clinicians who may encounter this serious but underrecognized cause of graft dysfunction and loss.

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.

Neonatal liver disease is a broad entity. When it presents in conjunction with other abnormalities, it raises the question of a potential underlying genetic cause. Etiologies that were once difficult to diagnose are becoming more readily identifiable with the arrival of next‐generation sequencing. We present a rare cause of neonatal liver disease, a FOCAD gene variant, that was determined to be the most likely cause of an infant’s liver disease and other findings. This case adds to only a few reports in the literature on this presentation in the neonatal period.

Background: The impact of social determinants of health (SDOH) on pediatric liver transplant outcomes has not been extensively investigated. The purpose of this study was to examine the effect of neighborhood‐level deprivation on graft and patient survival among pediatric liver transplant recipients.Methods: This is a single‐center observational study among children who received a primary liver transplant from March 1996 to March 2023. The Childhood Opportunity Index (COI) score was used to measure the degree of neighborhood deprivation.Results: A total of 252 children were included, half (52.8%) were female and the majority were non‐Hispanic White (71%). Half (53.6%) of the children had private insurance, and the median COI score was 64. A total of 28 children were transplanted from a very low‐to‐low COI area. Children in very low‐to‐low COI areas had worse patient (HR = 4.90, 95% CI = 1.41–17.04, p = 0.01) and graft (HR = 3.41, 95% CI = 1.19–9.75, p = 0.02) survival outcomes compared to children in moderate‐to‐very high areas when adjusting for clinical characteristics. COI score remained a significant predictor of graft survival after adjusting for race and insurance type (HR = 3.41, 95% CI = 1.12–10.40, p = 0.03).Conclusions: Pediatric liver transplant recipients from very low‐to‐low COI score areas have worse graft outcomes when accounting for clinical factors, race/ethnicity, and insurance status. Future research should investigate the impact of multiple, intersecting SDOH factors, rather than solely a collection of isolated variables.

Congenital dyserythropoietic anemia type 1 (CDA1) is an autosomal recessive disorder of ineffective erythropoiesis, resulting in increased iron storage. CDA1 is usually diagnosed in children and adolescents but can rarely present in the neonatal period with severe anemia at birth. There are no prior reports of neonatal liver histologic findings of CDA1. We report a case of CDA1 in a newborn presenting with severe anemia, cholestasis and liver failure, where liver biopsy helped confirm the diagnosis. A term infant, born via emergency Cesarean section, presented with cholestasis, hepatosplenomegaly, multiorgan failure and severe anemia at birth. A prior pregnancy was significant for fetal demise at 35 wk without autopsy or known etiology for the fetal demise. Parents are both healthy and there is no history of consanguinity. On further evaluation, the patient was found to have severe ferritin elevation and pulmonary hypertension. An extensive infectious and metabolic work-up was negative. Salivary gland biopsy was negative for iron deposition. At 2 wk of age, a liver biopsy showed findings consistent with CDA1. A genome rapid sequencing panel revealed novel variants in the CDAN1 gene. The patient's liver dysfunction, cholestasis and organomegaly resolved, however she remains transfusion-dependent. We report liver pathology findings of CDA1 with a novel genetic mutation for the first time in a newborn.