Pediatric Fulminant Hepatic Failure of Unknown Etiology – A Unique Immune Mediated Mechanism of CD8-Positive T-Cell Activation Causing Simultaneous Bone Marrow Suppression
Atsuko Nakazawa, Rie Irie, Kentaro Matsuoka, Seisuke Sakamoto, Mureo Kasahara. National Center for Child Health and Development, Tokyo, Japan; Kawasaki Municipal Hospital, Kawasaki, Japan
Background: In the vast majority of pediatric fulminant hepatic failure (FHF), the etiology of liver disease was unknown despite a series of studies for viral hepatitis, toxic or metabolic liver disease. The aim of this study is to characterize clinical and pathological features of FHF of unknown etiology (indeterminate FHF) in pediatric liver transplant population and to investigate a possible pathogenesis.
Design: From 2005 to 2011, 28 out of 161 pediatric liver transplants in National Center for Child Health and Development were FHF. Among FHF, 24 were of indeterminate etiology. The causes of other four recipients with FHF were viral infections (CMV, EBV, echo virus) and mitochondrial hepatopathy. The clinical information was obtained from medical record. Pathological analysis was performed using explanted liver and allograft. For immunohistochemistry, antibodies for anti-cCD3, CD4, CD8, CD20, CD56, perforin, TIA-1, FOXP3, and C4d were used.
Results: The median age at liver transplant was 10 month-old (range, 38 day to 148 month). 14 patients out of 24 (58%) were under 12 month-old. All patients showed pancytopenia and bone marrow examination revealed hypocellular marrow and macrophage activation with secondary hemophagocytosis. Explanted liver showed massive necrosis with lymphohistiocytic infiltration. CD8+T-cells were dominant population and infiltrated not only portal area but sinusoid. Eight patients (33%) including 22 biopsies demonstrated acute cellular rejection(ACR) with classic portal features. Seven patients (29%) including 34 biopsies demonstrated centrilobular injury. No ACR or centrilobular injury was seen in recipients with FHF of known causes. Idiopathic lobular hepatitis was seen in 10 recipients. Aplastic anemia (AA) developed in two recipients. A skewing pattern of HLA was observed.
Conclusions: Pediatric indeterminate FHF frequently occurred in young infant and presented massive necrosis with a striking CD8-positive T-cell accumulation in liver, bone marrow suppression, and refractory rejection with centrilobular injury. High incidence of AA in children with FHF and CD8+T-cell increase in peripheral blood of AA associated FHF were reported. Those observations strongly support the hypothesis that immune-mediated mechanism by activated CD8+T-cells is involved in the etiology of pediatric indeterminate FHF.
Wednesday, March 21, 2012 9:30 AM
Poster Session V # 239, Wednesday Morning