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Author Notes:

Sandy Feng, MD, PhD, Professor of Surgery in Residence, University of California San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143-0780, Telephone: (415) 353-8725, Fax: (415) 353 8709. sandy.feng@ucsf.edu,

Author contributions available in full text.

The authors would like to extend their appreciation towards all of the patients and their families that participated in this study.

We wish to thank the following: Sharon Blaschka; Crystal Lala; Kalpana Harish; Allan Kirk; Allison Priore; iWITH co-investigators and research coordinators; and the staff at all iWITH core laboratories for their contributions.

We acknowledge the support received by the National Institutes of Health’s (NIH) National Center for Advancing Translational Sciences from the following institutions: University of California, San Francisco, San Francisco, CA; Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL; Columbia University, New York, NY; Cincinnati Children’s Hospital, Cincinnati, OH; Children’s Hospital Colorado, Denver, CO; The Children’s Hospital of Philadelphia, Philadelphia, PA; St. Louis Children’s Hospital, St. Louis, MO and Emory University School of Medicine, Atlanta, GA.

A.M.J. is on the speakers’ bureau and receives honoraria from One Lambda. The authors disclose no other conflicts


Research Funding:

This research was primarily supported by U01-AI-100807 awarded by the National Institute of Allergy and Infectious Diseases (NIAID); and the National Institute for Diabetes and Digestive and Kidney Diseases.

In addition, the research was also performed as a project of the Clinical Trials in Organ Transplantation in Children (U01-AI-104347), a collaborative clinical research project headquartered at NIAID; and as a project of the Immune Tolerance Network (UM1AI109565), an international clinical research consortium headquartered at the Benaroya Research Institute; and supported by NIAID.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Gastroenterology & Hepatology
  • ALT
  • DSA
  • Immune Response
  • Prognostic Factor

Evidence of Chronic Allograft Injury in Liver Biopsies From Long-term Pediatric Recipients of Liver Transplants

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Journal Title:



Volume 155, Number 6


, Pages 1838-+

Type of Work:

Article | Post-print: After Peer Review


Background & Aims: A substantial proportion of pediatric liver transplant recipients develop subclinical chronic allograft injury. We studied whether there are distinct patterns of injury based on histopathologic features and identified associated immunologic profiles. Methods: We conducted a cross-sectional study of 157 stable, long-term pediatric recipients of transplanted livers (70 boys; > 6 years old at time of transplantation; mean, 8.9 ± 3.46 years after liver transplantation) who underwent liver biopsy analysis from August 13, 2012, through May 1, 2014. Participants had received livers from a living or deceased donor and had consistently normal results from liver tests. Liver biopsy specimens were scored by a central pathologist; an unsupervised hierarchical cluster analysis of histologic features was used to sort biopsy samples into 3 clusters. We conducted transcriptional and cytometric analyses of liver tissue samples and performed a systems biology analysis that incorporated clinical, serologic, histologic, and transcriptional data. Results: The mean level of alanine aminotransferase in participants was 27.6 ± 14.57 U/L, and the mean level of γ-glutamyl transferase was 17.4 ± 7.93 U/L. Cluster 1 was characterized by interface activity (n = 34), cluster 2 was characterized by periportal or perivenular fibrosis without interface activity (n = 45), and cluster 3 had neither feature (n = 78). We identified a module of genes whose expression correlated with levels of alanine aminotransferase, class II donor-specific antibody, portal inflammation, interface activity, perivenular inflammation, portal and perivenular fibrosis, and cluster assignment. The module was enriched in genes that regulate T-cell–mediated rejection (TCMR) of liver and other transplanted organs. Functional pathway analysis showed overrepresentation of TCMR gene sets for cluster 1 but not clusters 2 or 3. Conclusion: In an analysis of biopsies from an apparently homogeneous group of stable, long-term pediatric liver transplant recipients with consistently normal liver test results, we found evidence of chronic graft injury (inflammation and/or fibrosis). Biopsy samples with interface activity had a gene expression pattern associated with TCMR.

Copyright information:

© 2018 AGA Institute

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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