Date: Sunday, April 30, 2017
Session Name: Poster Session B: Pediatric Liver Transplant - Clinical
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall D1
Background: PALF requiring liver transplantation (LTx) often has no known etiology, and could result from undiagnosed metabolic disorders. Mitochondrial dysfunction is common in PALF, but it is unclear whether this is a cause or consequence of PALF. Methods: Whole transcriptome (RNA) sequencing was performed in liver tissue removed at LTx from four males with idiopathic PALF, median age 2.2 years (range 0.03-5.4), and compared with that seen in three pre-perfusion normal liver allograft biopsies. Differentially expressed genes (DEG) with fold-change cutoff >1.5 and q-value <0.05 were compared with those reported recently from the liver transcriptome of human HBV-induced ALF (Diaz, BMC, 2015) and Galactosamine/lipopolysaccharide-induced (toxic) ALF in mice (Chen, J Transl Med, 2015). Results: The 58 significant DEG in PALF liver tissue were enriched for coagulation factors, cytochrome, metabolic or synthetic enzymes, and inflammation. Four of 823 mitochondrial genes from the MitoCarta 2.0 database, PHYH, ALAS1, HMGCS2, and DHODH, were downregulated 6- to 12-fold in PALF and achieved technical replication with qRT-PCR (e.g., DHODH, -12-fold). Fifteen of 58 PALF genes were also differentially expressed in HBV-induced ALF and included downregulated mitochondrial (DHODH, HMGCS2), and coagulation/synthetic/drug metabolism genes (F13B, FGA, FGB, GYS2, GADD45G, MT1M, PGLYRP2, CYP1A2, CYP2C19, CYP4F2) and upregulated inflammatory genes, (CD8A-T-cells, CXCR4-chemokine, GPNMB-macrophage). Ten of 58 PALF genes were also differentially expressed in experimental (toxic) ALF in mice and included downregulated mitochondrial (Alas1, Acsm5) and coagulation/synthetic/drug metabolism genes (F13b, Gys2, Selenbl, Etnk2, Pttg1), and upregulated inflammatory and protein degradation genes (Cxcr4, Cxcl9, Ubd). Conclusions: The liver transcriptome of end-stage idiopathic PALF is characterized by enhanced cellular immune response, and impaired energy/general metabolism and synthetic function. Mitochondrial dysfunction which suggests impaired energy metabolism is not unique to PALF, and may represent global metabolic failure in dying hepatocytes.
Funding: Snow family.
CITATION INFORMATION: Ningappa M, McKiernan P, Squires R, Sun Q, Higgs B, Soltys K, Bond G, Ashokkumar C, Mazariegos G, Sindhi R. Inflammation, Impaired Energy Metabolism and Synthetic Failure Characterize the Liver Transcriptome of End-Stage Idiopathic Pediatric Acute Liver Failure (PALF). Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:Ningappa M, McKiernan P, Squires R, Sun Q, Higgs B, Soltys K, Bond G, Ashokkumar C, Mazariegos G, Sindhi R. Inflammation, Impaired Energy Metabolism and Synthetic Failure Characterize the Liver Transcriptome of End-Stage Idiopathic Pediatric Acute Liver Failure (PALF). [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/inflammation-impaired-energy-metabolism-and-synthetic-failure-characterize-the-liver-transcriptome-of-end-stage-idiopathic-pediatric-acute-liver-failure-palf/. Accessed November 17, 2019.
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