2016 - IPTA Fellows Meeting


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Mini Oral Abstract Presentations

18.62 - Indeterminate pediatric acute liver failure is characterized by dense CD8+ inflammation on liver biopsy

Presenter: Catherine, Chapin, Chicago, United States
Authors: Catherine Chapin, Estella Alonso, Hector Melin-Aldana, Peter Whitington

Indeterminate pediatric acute liver failure is characterized by a dense CD8 positive inflammatory infiltrate on liver biopsy

Catherine Chapin1, Estella Alonso1, Hector Melin-Aldana2, Peter Whitington1.

1Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Ann and Robert H. Lurie Children's Hospital, Chicago, IL, United States; 2Department of Anatomic Pathology, Ann and Robert H. Lurie Children's Hospital , Chicago, IL, United States

Introduction: Pediatric acute liver failure (PALF) is a devastating condition often resulting in death or liver transplantation (LT), and in which 45% of cases are of indeterminate (IND) etiology. Many of these IND cases may be initiated or driven by aberrant immune system activation, termed “immune dysregulation”. The aim of this study was to use immunohistochemical (IHC) staining to characterize the inflammatory infiltrate in liver biopsy specimens from IND PALF patients. We hypothesized that IND cases would have a more intense CD8+ lymphocyte and macrophage infiltrate compared to cases with a known diagnosis.  

Methods: PALF patients from 1999-2015 were retrospectively identified. Inclusion criteria included age 2-18 years, INR of  >1.5, and available archived liver specimens. Secondary causes of liver injury were excluded. Selected cases included both patients with known cause and IND diagnosis. Liver tissue from pediatric deceased LT donors served as a control group. Biopsies were prepared with IHC stains: CD8 (cytotoxic T lymphocytes), CD68 and CD163 (macrophages), CD34 (hematopoietic stem cells), and CD56 (natural killer T lymphocytes).  

Results: We identified 23 IND cases, 8 cases with diagnoses, and 4 donor controls for IHC staining. Median ages at diagnosis were 5.5 years (range 2-17yrs) for IND and 8.7 years (range 2-17yrs) for known disease cases (p=0.277). IND cases were predominantly male (74%) compared to known diagnoses (50%) (p=0.676). 61% of IND and 50% of diagnosed cases had undergone LT (p=0.689). CD8+ inflammatory infiltrate was dense in 83% (19/23), moderate in 4% (1/23), and minimal in 13% (3/23) of IND cases. Compared to 12% (1/8) with dense infiltrate and 88% (7/8) with minimal infiltrate in the diagnosed cases (p=0.0003). All donor controls had minimal CD8+ staining. There was no difference in macrophage staining between IND and diagnosed cases – all had dense CD163+ and CD68+ staining that correlated with degree of hepatocyte necrosis. Few CD56+ or CD34+ cells were seen in either IND or diagnosed cases.  

Discussion: Dense CD8+ staining was more common in PALF IND cases compared to known diagnoses, suggesting that cytotoxic T cells may play a role in the pathogenesis of IND PALF. Ours is the largest study to examine IHC staining of IND PALF cases, and the first to include both known diagnoses and healthy control groups for comparison. McKenzie et al described 9 IND PALF patients who had CD8+ staining on liver biopsy and improved with immunosuppressive therapy[1]. We suggest that liver biopsy with CD8 staining should be considered as part of the workup of IND PALF. Earlier identification of PALF cases with immune dysregulation and treatment with immunotherapy may improve transplant-free survival.  

Conclusion: Patients with IND PALF are more likely to have a CD8+ inflammatory infiltrate on liver biopsy compared to those with a known diagnosis.

References:

[1] McKenzie RB, Berquist WE, Nadeau KC et al. Novel protocol including liver biopsy to identify and treat CD8+ T-cell predominant acute hepatitis and liver failure. Pediatr Transplantation. 2014;18:503-509.


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