https://www.ncbi.nlm.nih.gov/pubmed/31228442 Biliary Atresia

Gastroenterology. 2019 Jun 13. pii: S0016-5085(19)41016-0. doi: 10.1053/j.gastro.2019.06.017. [Epub ahead of print]
Gene Expression Signatures Associated With Survival Times of Pediatric Patients With Biliary Atresia Identify Potential Therapeutic Agents.
Luo Z1, Shivakumar P1, Mourya R1, Gutta S1, Bezerra JA2.

Abstract

BACKGROUND & AIMS:
Little is known about the factors that affect outcomes of patients with biliary atresia and there are no medical therapies that increase biliary drainage.

METHODS:
Liver biopsies and clinical data were obtained from infants with cholestasis and from children without liver disease (controls); mRNA was isolated, randomly assigned to discovery (n=121) and validation sets (n=50), and analyzed by RNAseq. Using the Superpc R package followed by Cox regression analysis, we sought to identify gene expression profiles that correlated with survival without livertransplantation at 24 months of age. We also searched for combinations of gene expression patterns, clinical factors, and laboratory results obtained at diagnosis and at 1 and 3 months after surgery that associated with transplant-free survival for 24 months of age. We induced biliary atresia in BALB/c mice by intraperitoneal administration of Rhesus rotavirus type A. Mice were given injections of the anti-oxidants N-acetyl-cysteine (NAC) or manganese (III) tetrakis-(4-benzoic acid)porphyrin. Blood and liver tissues were collected and analyzed by histology and immunohistochemistry.

RESULTS:
We identified a gene expression pattern of 14 mRNAs associated with shorter vs longer survival times in the discovery and validation sets (P<.001). This gene expression signature, combined with level of bilirubin 3 months after hepatoportoenterostomy, identified children that survived for 24 months with an area under the curve value of 0.948 in the discovery set and 0.813 in the validation set (P<.001). Computer models correlated a cirrhosis-associated transcriptome with decreased times of transplant-free survival; this transcriptome included activation of genes that regulate the extracellular matrix and numbers of activated stellate cells and portal fibroblasts. Many mRNAs expressed at high levels in liver tissues from patients with 2-year transplant-free survival had enriched scores for glutathione metabolism. Among mice with biliary atresia given injections of anti-oxidants, only NAC reduced histologic features of liver damage and serum levels of aminotransferase, gamma-glutamyl transferase, and bilirubin. NAC also reduced bile duct obstruction and liver fibrosis and increased survival times.

CONCLUSIONS:
In studies of liver tissues from infants with cholestasis, we identified a 14-gene expression pattern that associated with transplant-free survival for 2 years. mRNAs encoding proteins that regulate fibrosis genes were increased in liver tissues from infants that did not survive for 2 years whereas mRNAs that encoded proteins that regulate glutathione metabolism were increased in infants that survived for 2 years. NAC reduced liver injury and fibrosis in mice with biliary atresia, and increased survival times. Agents such as NAC that promote glutathione metabolism might be developed for treatment of biliary atresia.