Novel protocol including liver biopsy to identify and treat CD8+ T‐cell predominant acute hepatitis and liver failure

Abstract

In the majority of children with ALF, the etiology is unknown and liver transplantation is often needed for survival. A patient case prompted us to consider that immune dysregulation may be the cause of indeterminate acute hepatitis and liver failure in children. Our study includes nine pediatric patients treated under a multidisciplinary clinical protocol to identify and treat immune-mediated acute liver injury. Patients with evidence of inflammation and no active infection on biopsy received treatment with intravenous immune globulin and methylprednisolone. Seven patients had at least one positive immune marker before or after treatment. All patients had a CD8+ T-cell predominant liver injury that completely or partially responded to immune therapy. Five of the nine patients recovered liver function and did not require liver transplantation. Three of these patients subsequently developed bone marrow failure and were treated with either immunosuppression or stem cell transplant. This series highlights the importance of this tissue-based approach to diagnosis and treatment that may improve transplant-free survival. Further research is necessary to better characterize the immune injury and to predict the subset of patients at risk for bone marrow failure who may benefit from earlier and stronger immunosuppressive therapy.

Indeterminate pediatric acute liver failure is uniquely characterized by a CD103+CD8+ T‐cell infiltrate

“…This study demonstrates that a histopathologic feature, specifically CD8 staining, differentiates iPALF from dPALF cases. Our findings agree with those of McKenzie et al, who published a case series of patients with iPALF (n = 7) and acute hepatitis (n = 2) thought to have immune dysregulation and found to have numerous CD8 + T‐cells on IHC staining of liver biopsies . Similarly, Patel et al reported a CD8 predominant T‐cell infiltrate on IHC staining of liver tissue from 5 patients with iPALF .…”

“…We found that all 3 iPALF patients in our study who developed AA and had peripheral blood flow cytometry available had a decreased CD4:CD8 ratio (due to an increase in CD8 cells), and this finding has been reported in other studies of hepatitis‐associated AA . In McKenzie et al, all iPALF and acute hepatitis patients had a low CD4:CD8 ratio by peripheral blood flow cytometry, 3 of whom developed AA . We propose that a low CD4:CD8 ratio is an additional biomarker of the iPALF immune dysregulation phenotype as well as of those iPALF patients who are more likely to develop AA.…”

“…In our series, 8 iPALF patients received intravenous steroids for treatment of presumed immune dysregulation. The only published experience of treating pediatric iPALF patients with steroids specifically for their liver dysfunction is by McKenzie et al, in which patients were given intravenous immunoglobulin and methylprednisolone and all reportedly improved (decrease in alanine aminotransferase and total bilirubin), with 3 undergoing LT and 5 recovering with their native liver . When considering steroid therapy for children with ALF, it is important to note that the majority of studies in adult patients with ALF have failed to show any survival benefit of steroid treatment .…”

“…Patients in this group, called indeterminate PALF (iPALF), have worse outcomes and are more likely to undergo liver transplantation (LT) than those with known diagnosis (dPALF) . To date, little is known about the pathophysiology of iPALF, but growing evidence supports the hypothesis that the liver injury is immune‐mediated, resulting from an imbalance between proinflammatory and anti‐inflammatory factors . iPALF patients frequently exhibit signs of immune activation and dysregulation including cytopenias, elevated soluble interleukin‐2 receptor levels, natural killer cell dysfunction, and development of aplastic anemia (AA) either shortly before or after their liver injury.…”

Pediatric acute liver failure of undetermined cause: A research workshop

“…Patients with iPALF have a liver injury pattern similar to observations in familial and sporadic HLH and MAS . However, iPALF patients do not manifest the full spectrum of criteria required for diagnosis of HLH.…”