Late graft hepatitis and fibrosis in pediatric liver allograft recipients: Current concepts and future developments

Abstract

Liver transplantation (LT) in children now has a 20-year survival of >80%, but the longterm outcome of these grafts remains uncertain. Serial protocol liver biopsies after transplantation from several pediatric centres have demonstrated the gradual development of unexplained graft inflammation ("idiopathic" posttransplant hepatitis; IPTH) and graft fibrosis in biopsies obtained >12 months post-LT in children with good graft function and (near) normal liver biochemistry. Although the clinical significance of these findings is uncertain, there is evidence to suggest that IPTH may be a form of rejection or chronic antibody-mediated rejection as it is associated with the presence of auto/alloantibodies; de novo Class II donor-specific HLA antibodies (DSA); previous episodes of rejection, and may improve or be prevented with increased immunosuppression. Currently, the only method of diagnosing either hepatitis or fibrosis has been by serial protocol biopsies as neither serum markers of fibrosis nor noninvasive methods to detect fibrosis such as transient elastography (TE) are sufficiently validated in children. This review will focus on the diagnosis and management of idiopathic posttransplant hepatitis and graft fibrosis, discuss current methods for detecting graft injury, and potential mechanisms for their development. Liver Transplantation 22 1593-1602 2016 AASLD.

Late allograft fibrosis in pediatric liver transplant recipients: Assessed by histology and transient elastography

“…Unfortunately, DSAs were not studied in our patients. Further studies are required to clarify the role of DSAs and other predictive factors of allograft fibrosis …”

Class II Human Leukocyte Antigen Epitope Mismatch Predicts De Novo Donor‐Specific Antibody Formation After Liver Transplantation

“…The adverse impact of human leukocyte antigen (HLA) donor‐specific antibodies (DSAs) in liver transplantation (LT) recipients is already established . Many studies have demonstrated associations between de novo donor‐specific antibody (dn‐DSA) with liver allograft injury .…”

Longterm outcome of the liver graft: The pathologist's perspective

“…Considerable attention has been placed on structural integrity of liver allografts (especially pediatric) because of expectation of decades of morbidity‐free survival . Most studies in pediatric recipients, where primary disease recurrence is not a significant issue, show a high (>40%) incidence of histopathologically significant inflammation and progressive fibrosis by 5‐10 years after transplantation .…”

“…Considerable attention has been placed on structural integrity of liver allografts (especially pediatric) because of expectation of decades of morbidity‐free survival . Most studies in pediatric recipients, where primary disease recurrence is not a significant issue, show a high (>40%) incidence of histopathologically significant inflammation and progressive fibrosis by 5‐10 years after transplantation . Substantial evidence associates allograft inflammation and fibrosis with smoldering allo‐immunological injury (combined T cell–mediated rejection [TCMR] and chronic antibody‐mediated rejection [cAMR]) as underlying causes .…”

“…Because biliary atresia and metabolic and autoimmune disorders remain as the leading indications in children, therapeutic advancements have had less of an impact on these aspects of liver transplantation . Nevertheless, there is increasing attention in both adults and pediatric patients to longterm allograft and patient health and risk factors that might adversely impact decades‐long, morbidity‐free survival …”