Non-inflammatory centrilobular sinusoidal fibrosis in pediatric liver transplant recipients under tacrolimus withdrawal

Aim: We hypothesized that non-inflammatory central sinusoidal fibrosis (NICSF) is a sign of inadequate immunosuppression in children after living-donor liver transplantation. Methods: In study 1, liver biopsy specimens of 158 patients who had undergone liver transplantation 10 years before or earlier were examined to study the relationship between NICSF and tacrolimus withdrawal. In study 2, tacrolimus was resumed in 18 patients with NICSF in follow-up biopsies after tacrolimus withdrawal and the subsequent histological changes were analyzed. Results: In study 1, after excluding 95 patients with ongoing vascular, biliary and immunological complications, 47 of 63 patients (75%) had NICSF and significant (P = 0.0285) contributing factors were found to be episodes of tacrolimus withdrawal. In study 2, during withdrawal, tacrolimus administration had been discontinued in nine, reduced to once per month in three, twice per month in two, once a week in two and twice a week in two patients, and then finally resumed to daily administration in all. NICSF was scored as 4 in one, 3 in seven, 2 in four and 1 in six patients using modified Dixon's criteria (score, 04). After resumption, NICSF was improved in six, unchanged in 11 and aggravated in one patient. C4d deposition was improved in all NICSF-improved patients. Incidence of positive C4d prior to resumption was significantly greater in improved patients than non-improved patients (P = 0.0245). Conclusion: NICSF might be an indicator of inadequate immunosuppression in long-term followed recipients and its mechanism may be due to immune reactions including humoral immunity.