TY - JOUR
T1 - Staging of biliary atresia at diagnosis by molecular profiling of the liver
AU - Moyer, Katie
AU - Kaimal, Vivek
AU - Pacheco, Cristina
AU - Mourya, Reena
AU - Xu, Huan
AU - Shivakumar, Pranavkumar
AU - Chakraborty, Ranajit
AU - Rao, Marepalli
AU - Magee, John C.
AU - Bove, Kevin
AU - Aronow, Bruce J.
AU - Jegga, Anil G.
AU - Bezerra, Jorge A.
N1 - Funding Information:
This work was funded by the following grants from the National Institutes of Health: DK083781 and DK062497 (to JAB) and DK078392 (Gene Expression and Sequencing Core and Bioinformatics Core, Digestive Disease Research Core Center in Cincinnati). We thank Dr William Balistreri for insightful review of the manuscript. We also thank the Witzigreuter Family for support of liver research, the Data Coordinating Center of the NIDDK-funded Biliary Atresia Research Consortium (BARC) and the Principal Investigators and Clinical Research Coordinators of individual BARC Centers for patient recruitment and acquisition of tissue and data. The contents of the article do not necessarily reflect the opinions or views of the NIDDK, BARC, or BARC investigators.
PY - 2010/5/13
Y1 - 2010/5/13
N2 - Background: Young age at portoenterostomy has been linked to improved outcome in biliary atresia, but pre-existing biological factors may influence the rate of disease progression. In this study, we aimed to determine whether molecular profiling of the liver identifies stages of disease at diagnosis.Methods: We examined liver biopsies from 47 infants with biliary atresia enrolled in a prospective observational study. Biopsies were scored for inflammation and fibrosis, used for gene expression profiles, and tested for association with indicators of disease severity, response to surgery, and survival at 2 years.Results: Fourteen of 47 livers displayed predominant histological features of inflammation (N = 9) or fibrosis (N = 5), with the remainder showing similar levels of both simultaneously. By differential profiling of gene expression, the 14 livers had a unique molecular signature containing 150 gene probes. Applying prediction analysis models, the probes classified 29 of the remaining 33 livers into inflammation or fibrosis. Molecular classification into the two groups was validated by the findings of increased hepatic population of lymphocyte subsets or tissue accumulation of matrix substrates. The groups had no association with traditional markers of liver injury or function, response to surgery, or complications of cirrhosis. However, infants with an inflammation signature were younger, while those with a fibrosis signature had decreased transplant-free survival.Conclusions: Molecular profiling at diagnosis of biliary atresia uncovers a signature of inflammation or fibrosis in most livers. This signature may relate to staging of disease at diagnosis and has implications to clinical outcomes.
AB - Background: Young age at portoenterostomy has been linked to improved outcome in biliary atresia, but pre-existing biological factors may influence the rate of disease progression. In this study, we aimed to determine whether molecular profiling of the liver identifies stages of disease at diagnosis.Methods: We examined liver biopsies from 47 infants with biliary atresia enrolled in a prospective observational study. Biopsies were scored for inflammation and fibrosis, used for gene expression profiles, and tested for association with indicators of disease severity, response to surgery, and survival at 2 years.Results: Fourteen of 47 livers displayed predominant histological features of inflammation (N = 9) or fibrosis (N = 5), with the remainder showing similar levels of both simultaneously. By differential profiling of gene expression, the 14 livers had a unique molecular signature containing 150 gene probes. Applying prediction analysis models, the probes classified 29 of the remaining 33 livers into inflammation or fibrosis. Molecular classification into the two groups was validated by the findings of increased hepatic population of lymphocyte subsets or tissue accumulation of matrix substrates. The groups had no association with traditional markers of liver injury or function, response to surgery, or complications of cirrhosis. However, infants with an inflammation signature were younger, while those with a fibrosis signature had decreased transplant-free survival.Conclusions: Molecular profiling at diagnosis of biliary atresia uncovers a signature of inflammation or fibrosis in most livers. This signature may relate to staging of disease at diagnosis and has implications to clinical outcomes.
UR - http://www.scopus.com/inward/record.url?scp=78751681685&partnerID=8YFLogxK
U2 - 10.1186/gm154
DO - 10.1186/gm154
M3 - Article
C2 - 20465800
AN - SCOPUS:78751681685
SN - 1756-994X
VL - 2
JO - Genome Medicine
JF - Genome Medicine
IS - 5
M1 - 33
ER -