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Gastroenterology. 2018 Dec;155(6):1838-1851.e7. doi: 10.1053/j.gastro.2018.08.023. Epub 2018 Aug 23.

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

Author information

1
Division of Transplantation, Department of Surgery, University of California San Francisco, San Francisco, California. Electronic address: sandy.feng@ucsf.edu.
2
Pediatric Liver Care Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
3
Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
4
The Immune Tolerance Network, Bethesda, Maryland.
5
Rho, Inc, Chapel Hill, North Carolina.
6
Section of Transplant Surgery, Department of Surgery, University of Michigan, Ann Arbor, Michigan.
7
Biomedical Research Center in Hepatic and Digestive Diseases, Carlos III Health Institute, Barcelona, Spain.
8
Siragusa Transplantation Center, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.
9
Department of Pathology, Emory University Hospital, Atlanta, Georgia.
10
Transplantation Branch, Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, Rockville, Maryland.
11
Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland; Department of Pathology, Emory University Hospital, Atlanta, Georgia.
12
Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia.
13
Section of Gastroenterology, Hepatology, and Nutrition, Texas Children's Hospital, Houston, Texas.
14
Division of Immunogenetics and Transplantation Immunology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland.
15
Center for Liver Diseases and Transplantation, Department of Surgery, Columbia University Medical Center, New York, New York.
16
Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania.
17
Division of Pediatric Gastroenterology, Hepatology and Nutrition, Transplant and Regenerative Medicine Center, Toronto, Ontario, Canada.
18
Liver Transplant Program, The Children's Hospital of Pennsylvania, Philadelphia, Pennsylvania.
19
Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado.
20
Division of Gastroenterology, Hepatology, and Nutrition, St. Louis Children's Hospital, St. Louis, Missouri.
21
Institute of Liver Studies, King's College, London, London, United Kingdom.

Abstract

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.

KEYWORDS:

ALT; DSA; Immune Response; Prognostic Factor

PMID:
30144432
PMCID:
PMC6279538
[Available on 2019-12-01]
DOI:
10.1053/j.gastro.2018.08.023

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