title: Protocol liver biopsy is the only examination that can detect mid-term graft fibrosis after pediatric liver transplantation.
abstract: OBJECTIVE
  To assessed the clinical significance of protocol liver biopsy (PLB) in pediatric liver transplantation (LT).
  
  
  METHODS
  Between July 2008 and August 2012, 89 and 55 PLBs were performed in pediatric patients at two and five years after LT, respectively. We assessed the histopathological findings using the Metavir scoring system, including activity (A) and fibrosis (F), and we identified factors associated with scores of ≥ A1 and ≥ F1. Our results clarified the timing and effectiveness of PLB.
  
  
  RESULTS
  The incidences of scores of ≥ A1 and ≥ F1 were 24.7% and 24.7%, respectively, at two years after LT and 42.3% and 34.5%, respectively, at five years. Independent risk factors in a multivariate analysis of a score of ≥ A1 at two years included ≥ 2 h of cold ischemic time, no acute cellular rejection and an alanine amino transaminase (ALT) level of ≥ 20 IU/L (P = 0.028, P = 0.033 and P = 0.012, respectively); however, no risk factors were identified for a score of ≥ F1. Furthermore, no independent risk factors associated with scores of ≥ A1 and ≥ F1 at five years were identified using multivariate analysis. A ROC curve analysis of ALT at two years for a score of ≥ A1 demonstrated the recommended cutoff value for diagnosing ≥ A1 histology to be 20 IU/L. The incidence of scores of ≥ A2 or ≥ F2 at two years after LT was 3.4% (three cases), and all patients had an absolute score of ≥ A2. In contrast to that observed for PLBs at five years after LT, the incidence of scores of ≥ A2 or ≥ F2 was 20.0% (11 cases), and all patients had an absolute score of ≥ F2. In all cases, the dose of immunosuppressants was increased after the PLB, and all ten patients who underwent a follow-up liver biopsy improved to scores of ≤ A1 or F1.
  
  
  CONCLUSIONS
  PLB at two years after LT is an unnecessary examination, because the serum ALT level reflects portal inflammation. In addition, immunosuppressive therapy should be modulated to maintain the ALT concentration at a level less than 20 IU/L. PLB at five years is an excellent examination for the detection of early reversible graft fibrosis because no serum markers reflect this finding.
authors.affiliation: Yukihiro Sanada, Taizen Urahashi, Yoshiyuki Ihara, Taiichi Wakiya, Noriki Okada, Naoya Yamada, Yuta Hirata, Koichi Mizuta, Department of Transplant Surgery, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Sanada
authors.affiliation: Yukihiro Sanada, Taizen Urahashi, Yoshiyuki Ihara, Taiichi Wakiya, Noriki Okada, Naoya Yamada, Yuta Hirata, Koichi Mizuta, Department of Transplant Surgery, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Koshi
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Yukihiro Sanada, Taizen Urahashi, Yoshiyuki Ihara, Taiichi Wakiya, Noriki Okada, Naoya Yamada, Yuta Hirata, Koichi Mizuta, Department of Transplant Surgery, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Taizen
authors.initials: T
authors.lastname: Urahashi
authors.affiliation: Yukihiro Sanada, Taizen Urahashi, Yoshiyuki Ihara, Taiichi Wakiya, Noriki Okada, Naoya Yamada, Yuta Hirata, Koichi Mizuta, Department of Transplant Surgery, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ihara
authors.affiliation: Yukihiro Sanada, Taizen Urahashi, Yoshiyuki Ihara, Taiichi Wakiya, Noriki Okada, Naoya Yamada, Yuta Hirata, Koichi Mizuta, Department of Transplant Surgery, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Taiichi
authors.initials: T
authors.lastname: Wakiya
authors.affiliation: Yukihiro Sanada, Taizen Urahashi, Yoshiyuki Ihara, Taiichi Wakiya, Noriki Okada, Naoya Yamada, Yuta Hirata, Koichi Mizuta, Department of Transplant Surgery, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Noriki
authors.initials: N
authors.lastname: Okada
authors.affiliation: Yukihiro Sanada, Taizen Urahashi, Yoshiyuki Ihara, Taiichi Wakiya, Noriki Okada, Naoya Yamada, Yuta Hirata, Koichi Mizuta, Department of Transplant Surgery, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Yamada
authors.affiliation: Yukihiro Sanada, Taizen Urahashi, Yoshiyuki Ihara, Taiichi Wakiya, Noriki Okada, Naoya Yamada, Yuta Hirata, Koichi Mizuta, Department of Transplant Surgery, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Hirata
authors.affiliation: Yukihiro Sanada, Taizen Urahashi, Yoshiyuki Ihara, Taiichi Wakiya, Noriki Okada, Naoya Yamada, Yuta Hirata, Koichi Mizuta, Department of Transplant Surgery, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Mizuta
mesh_terms: D000293:Adolescent; D001706:Biopsy / Q000379:methods*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005355:Fibrosis / Q000503:physiopathology; D006084:Graft Rejection; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D007249:Inflammation; D008099:Liver / Q000473:pathology*; D008103:Liver Cirrhosis / Q000175:diagnosis* / Q000473:pathology; D017093:Liver Failure / Q000175:diagnosis / Q000453:epidemiology; D008111:Liver Function Tests; D016031:Liver Transplantation; D008297:Male; D009367:Neoplasm Staging; D012372:ROC Curve; D012307:Risk Factors; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents
keywords: Graft fibrosis; Immunosuppression; Liver function test; Pediatric liver transplantation; Protocol liver biopsy