RESUMO
OBJECTIVE: To describe the usefulness of rapid whole genome sequencing (rWGS) in a cohort of children presenting with acute liver dysfunction. STUDY DESIGN: This was a retrospective, population-based cohort study conducted at Primary Children's Hospital in Salt Lake City, Utah. Children meeting criteria for acute liver dysfunction who received rWGS between August 2019 and December 2021 were included. rWGS was performed on blood samples from the patient and parents (1 or both depending on availability). The clinical characteristics of patients with positive rWGS results were compared with those with negative results. RESULTS: Eighteen patients with pediatric acute liver dysfunction who had rWGS were identified. The median turnaround time from the date rWGS testing was ordered to the date an initial report was received was 8 days with a shorter turnaround time in patients with a diagnostic rWGS (4 days vs 10 days; P = .03). A diagnostic result was identified in 7 of 18 patients (39%). Subsequently, 4 patients in this cohort, who had negative rWGS results, were found to have a toxic exposure accounting for their liver dysfunction. With removal of these patients, the diagnostic rate of rWGS was 7 of 14 (50%). The use of rWGS led to a change in management for 6 of 18 patients (33%). CONCLUSIONS: We found that rWGS provided a diagnosis in up to 50% of pediatric acute liver dysfunction. rWGS allows for higher diagnostic rates in an expedited fashion that affects clinical management. These data support the routine use of rWGS for life-threatening disorders in children, specifically acute liver dysfunction.
Assuntos
Hepatopatias , Criança , Humanos , Lactente , Estudos Retrospectivos , Estudos de Coortes , Sequenciamento Completo do Genoma/métodos , Mapeamento CromossômicoRESUMO
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.
Assuntos
Falência Hepática Aguda , Lactente , Recém-Nascido , Humanos , Criança , Falência Hepática Aguda/genética , Fibrose , Biomarcadores/análise , ChicagoRESUMO
OBJECTIVES: To investigate the prevalence of hemophagocytic lymphohistiocytosis (HLH) syndrome in pediatric acute liver failure (PALF) of infancy and assess the diagnostic role of rapid immunologic tests, genotype/phenotype correlations, and clinical outcomes. STUDY DESIGN: We retrospectively analyzed 78 children with PALF aged <24 months referred over almost 2 decades. The studied patients with a phenotype of HLH syndrome had a comprehensive immunologic workup, including additional genetic analysis for primary immunologic causes. RESULTS: Thirty of the 78 children had the HLH phenotype and underwent genetic assessment, which demonstrated positive findings in 19 (63.3%), including 9 (30%) with biallelic primary HLH mutations and 10 (33.3%) with heterozygous mutations and/or polymorphisms. The most common form of primary HLH was familial hemophagocytic lymphohistiocytosis (FHL)-2, diagnosed in 6 children, 4 of whom had a c.50delT (p.Leu17ArgfsTer34) mutation in the PRF1 gene. Three patients with primary HLH received genetic diagnoses of FHL-3, Griscelli syndrome, and LRBA (lipopolysaccharide-responsive vesicle trafficking, beach- and anchor-containing) protein deficiency. Overall mortality in the series was 52.6% (10 of 19), and mortality in children with a documented biallelic pathogenic HLH mutation (ie, primary HLH) was 66.6% (6 of 9). Two children underwent liver transplantation, and 4 children underwent emergency hematopoietic stem cell transplantation; all but 1 child survived medium term. CONCLUSIONS: Primary HLH can be diagnosed retrospectively in approximately one-third of infants with indeterminate PALF (iPALF) who meet the clinical criteria for HLH, often leading to their death. The most common HLH type in iPALF is FHL-2, caused by biallelic mutations in PRF-1. The clinical relevance of observed heterozygous mutations and variants of uncertain significance requires further investigation. Prompt hematopoietic stem cell transplantation could be life-saving in infants who survive the liver injury.
Assuntos
Falência Hepática Aguda , Linfo-Histiocitose Hemofagocítica , Humanos , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/epidemiologia , Perforina/genética , Estudos Retrospectivos , Prevalência , Mutação , Falência Hepática Aguda/diagnóstico , Falência Hepática Aguda/epidemiologia , Falência Hepática Aguda/etiologia , Proteínas Adaptadoras de Transdução de Sinal/genéticaRESUMO
Pediatric acute liver failure (PALF) due to mushroom poisoning is a rare and life-threatening disease. There is no specific treatment. Plasma exchange (PE) is often used as a bridge to the regeneration of the liver or transplantation. However, PE is limited due to an inadequate plasma supply and transfusion-related risks. The double plasma molecular adsorption system (DPMAS) can adsorb toxins, including bilirubin and inflammatory mediators. However, the DPMAS cannot improve coagulation disorders. Combining PE and the DPMAS could compensate for the shortcomings of the two techniques. A previous study showed that the combination might be more effective than using PE or the DPMAS alone in patients with mild acute-on-chronic liver failure. To the best of our knowledge, few studies combined PE and the DPMAS for the treatment of PALF due to mushroom poisoning. Here, we specifically describe our experience with PE and the DPMAS in PALF. In conclusion, our study shows that the DPMAS and PE are safe and effective in reducing the bilirubin level and improving blood coagulation in PALF due to mushroom poisoning as a bridge to transplantation or recovery.