Centrilobular fibrosis in long-term follow-up of pediatric liver transplant recipients.

BACKGROUND: Centrilobular fibrosis after liver transplant in adults is caused mainly by viral hepatitis, chronic rejection, and azathioprine toxicity. The aim of this study was to investigate possible etiologies and the long-term outcome of this lesion in children.
METHODS: We identified centrilobular fibrosis in 12 of 117 pediatric liver transplant recipients who were investigated for persistent elevations in aminotransferases. Etiologic factors, histologic features on serial biopsies, and clinical and biochemical changes over time were noted for 8 recipients in whom a readily identifiable cause was not apparent.
RESULTS: Centrilobular fibrosis developed a mean of 1.7 years (range: 30 days-3.6 years) posttransplantation in patients receiving cyclosporine, azathioprine, and prednisone. Centrilobular fibrosis was always associated with portal fibrosis and, in six recipients, with persistent, low-grade, cellular rejection. None demonstrated chronic cholestasis, ductopenia, or identifiable vasculopathy. Ischemic, viral, and autoimmune etiologies were excluded. Discontinuing azathioprine did not lead to biochemical or histological improvement. After changing to tacrolimus, aminotransferases normalized in three recipients and repeat biopsies in six were unchanged during a further 2 years of follow-up.
CONCLUSIONS: Centrilobular fibrosis may develop in a small number of pediatric liver transplant recipients, resulting in considerable difficulties in biopsy interpretation. It is not associated with viral hepatitis nor with classical features of chronic rejection. The prognostic significance of centrilobular fibrosis is uncertain, although no child has required retransplantation in up to 12 years of follow-up. A role for a low-grade, chronic form of cellular rejection heralded by persistent, variable, and otherwise unexplained elevations in aminotransferases is suggested.