RNA-Sequencing Analysis Identifies Etiology Specific Transcriptional Signatures in Neonatal Acute Liver Failure.

OBJECTIVE: To assess hepatic transcriptional signatures in infants with gestational alloimmune liver disease (GALD) compared with other etiologies of neonatal acute liver failure (ALF) and older pediatric patients with ALF. STUDY DESIGN: Neonates with ALF (international normalized ratio ≥2 within 30 days of life) and deceased neonates without liver disease (<30 days of age) with available liver tissue between 2010 and 2021 were identified at Ann & Robert H. Lurie Children's Hospital of Chicago. Clinical information, liver histology, and data from RNA-sequencing analysis was compared between neonates with GALD, non-GALD etiologies of neonatal ALF, and nondiseased neonatal liver. RESULTS: Quantification of trichrome staining showed an increase in fibrosis in patients with GALD vs those with non-GALD neonatal ALF (P = .012); however, quantification of α-cytokeratin 19-positive ductules did not differ between groups (P = .244). Gene set enrichment analysis of RNA-sequencing data identified the pathways of complement activation, fibrosis, and organogenesis to be upregulated in patients with GALD with ALF. In contrast, patients with non-GALD causes of neonatal ALF had increased gene expression for interferon-driven immune pathways. Individual genes upregulated in GALD included matrix metallopeptidase 7, hepatocyte growth factor, and chemokine ligand 14. CONCLUSIONS: We have identified distinct pathways that are significantly upregulated in patients with GALD and potential disease-specific diagnostic biomarkers. Future studies will aim to validate these findings and help identify GALD-specific diagnostic biomarkers to improve diagnostic accuracy and reduce GALD-associated patient mortality.

Applying an Age-specific Definition to Better Characterize Etiologies and Outcomes in Neonatal Acute Liver Failure.

OBJECTIVE: Neonatal acute liver failure (ALF) is a rare disease with high mortality for which no standard age-specific definition exists. To advance the understanding of neonatal ALF, we characterize the etiology, presenting features, treatment, and outcomes in infants within 1 month of life. METHODS: We performed a single-center 11-year retrospective chart review of neonates ≤30 days of life with ALF as defined by an INR of ≥2.0. Comparisons were made by etiology and survival with native liver (SNL). Estimated survival was performed using the Kaplan-Meier method. RESULTS: Forty-three patients met inclusion criteria for neonatal ALF. Etiologies included viral infection (23%), gestational alloimmune liver disease with neonatal hemochromatosis (GALD-NH) (21%), cardiac-associated ischemia (16%), other ischemia (14%), genetic etiologies (9%), Trisomy 21-associated myelodysplasia (TAM) (7%), hemophagocytic lymphohistiocytosis (HLH) (2%), and not identified (7%). Infants with viral etiologies had the highest alanine aminotransferase (ALT) at presentation (1179 IU/L, interquartile range [IQR] 683-1585 IU/L) in contrast to low levels in GALD-NH (23 IU/L, IQR 18-64 IU/L). Across all etiologies, only 33% were alive at 1 year. Overall median survival was 74 days; 17 days for viral infection and 74 days for GALD-NH. Among laboratory values at presentation, alpha-fetoprotein (AFP) was significantly higher in patients that survived with their native liver (P = 0.04). CONCLUSIONS: Overall, outcome for neonatal ALF is poor. Although initial laboratory values can differentiate viral infection or GALD-NH, further studies are needed to identify laboratory parameters that predict SNL by etiology to ultimately improve patient outcomes.