Indirect immunohistochemical evaluation of graft fibrosis and interface hepatitis after pediatric liver transplantation

Abstract

Fibrosis or IH following pediatric liver transplantation is recognized as major causes of graft loss, but the etiology remains unclear. To determine this issue, we used an indirect immunohistochemistry technique with post-transplant serum samples from recipients and normal human liver tissues from living liver donors, and the association between occult antibody reaction to the liver and the occurrence of fibrosis or IH was evaluated. Forty-three recipients were evaluated, and both hepatocytes and biliary epithelial cells were evaluated for staining intensity. Fibrosis and IH occurred in 13 and six patients, respectively. According to staining results for the hepatocytes and biliary epithelial cells, 18 and 11 patients, respectively, were classified into the positive group. According to log-rank analysis, positive reaction for hepatocytes was associated with increased rates of fibrosis and IH (p = 0.002 and 0.048, respectively), while positive reaction for biliary epithelial cells was associated with an increased rate of fibrosis (p = 0.014). Multivariate analysis revealed that positive reaction for hepatocytes and biliary epithelial cells was independently associated with fibrosis occurrence (p = 0.020 and 0.047, respectively). In conclusion, immune-mediated reactions by occult antibodies may underlie the pathogeneses of fibrosis and IH.

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

“…This particularly applies to the pediatric population, in whom recurrent disease can largely be excluded as a cause of late graft dysfunction. Evidence in support of this suggestion includes the following: The frequent presence of autoantibodies/alloantibodies as well as other uncharacterized serum factors, which may react with donor hepatocytes and/or bile ducts The observation that previous episodes of rejection are a risk factor for IPTH …”

“…The frequent presence of autoantibodies/alloantibodies as well as other uncharacterized serum factors, which may react with donor hepatocytes and/or bile ducts. (3,14,20) 2. The observation that previous episodes of rejection are a risk factor for IPTH.…”

What is the long-term outcome of the liver allograft?

“…Many paediatric cases are associated with the development of autoantibodies [12] or uncharacterized serum factors reacting with normal hepatocytes and/or biliary epithelial cells [139] or with features suggestive of rejection [135], suggesting that this is likely to represent a form of immune-mediated graft damage. This hypothesis is supported by the observation that treatment of IPTH with increased immunosuppression may prevent fibrosis progression [140] and by the suggestion, discussed earlier, that late rejection may present with ''hepatitic features'' resembling chronic viral or autoimmune hepatitis.…”

Importance of liver biopsy findings in immunosuppression management: Biopsy monitoring and working criteria for patients with operational tolerance

“…Several protocol biopsy–based studies have clearly shown an association between progressive liver fibrosis and IPTH,52, 53 which might represent a hepatitic variant of rejection53 or de novo AIH 54‐59. This is in contrast to other studies attributing progressive fibrosis in pediatric recipients to late manifestations of early technical or transplant‐related factors such as biliary strictures,50 cellular rejection,54, 60, 61 and late‐onset indolent antibody‐mediated rejection (AMR) 62. Late‐onset rejection with hepatitic features, IPTH, and de novo AIH are generally considered to be distinct entities, but emerging evidence suggests that they might contribute to an overlapping spectrum of immune‐mediated injury in long‐term survivors 39, 63.…”