King's College London

Molecular diagnosis of rejection is emerging in kidney, heart, and lung transplant biopsies and could offer insights for liver transplant biopsies. We measured gene expression by microarrays in 235 liver transplant biopsies from 10 centers. Unsupervised archetypal analysis based on expression of previously annotated rejection-related transcripts identified 4 groups: normal “R1_normal” (N = 129), T cell–mediated rejection (TCMR) “R2_TCMR” (N = 37), early injury “R3_injury” (N = 61), and fibrosis “R4_late” (N = 8). Groups differed in median time posttransplant, for example, R3_injury 99 days vs R4_late 3117 days. R2_TCMR biopsies expressed typical TCMR-related transcripts, for example, intense IFNG-induced effects. R3_injury displayed increased expression of parenchymal injury transcripts (eg, hypoxia-inducible factor EGLN1). R4_late biopsies showed immunoglobulin transcripts and injury-related transcripts. R2_TCMR correlated with histologic rejection although with many discrepancies, and R4_late with fibrosis. R2_TCMR, R3_injury, and R4_late correlated with liver function abnormalities. Supervised classifiers trained on histologic rejection showed less agreement with histology than unsupervised R2_TCMR scores. No confirmed cases of clinical antibody-mediated rejection (ABMR) were present in the population, and strategies that previously revealed ABMR in kidney and heart transplants failed to reveal a liver ABMR phenotype. In conclusion, molecular analysis of liver transplant biopsies detects rejection, has the potential to resolve ambiguities, and could assist with immunosuppressive management.