Single center retrospective studies report variable inflammation and progressive fibrosis in long-term pediatric liver allografts. In preliminary work as part of the IWITH trial (section D), we rigorously described and analyzed structural changes in liver allografts in a multi-center cohort of stable children with ALT and GGT <50IU/L.
Screening, pre-weaning liver biopsies done at 12 North American centers in an immunosuppression withdrawal study for children ≥4ys post-transplant were scored by a central pathologist for 48 histologic criteria. Hierarchical cluster analysis was performed on three dominant features: 1) periportal/portal fibrosis 2) perivenular fibrosis 3) interface activity. Multivariable logistic regression analysis with clinical covariates and backward variable selection (p<0.10 for retention) identified independent predictors of cluster assignment. Biopsies segregated into 3 distinct clusters : 1 no fibrosis no interface activity (n=52); 2 fibrosis but no interface activity (n=32); 3 interface activity +/- fibrosis (n=16).
We conclude that long-term pediatric liver transplant recipients with normal liver tests can harbor significant structural changes with/without inflammation. Distinct structural clusters and their clinical correlates suggest both non-immune and immune mechanisms of histologic allograft deterioration. Future data, including C4d score, donor specific antibody, and tolerant/non-tolerant phenotype, currently in analyses may confirm the mechanism of injury and guide future therapeutic trials.