Molecular injury phenotypes in human liver transplant biopsies: The INTERLIVER Study

Document Type

Conference Proceeding

Publication Date


Publication Title



Purpose: The many sources of liver parenchymal injury are difficult to evaluate by histology but could be amenable to molecular assessment. Having recently developed a molecular microscope diagnostic system (MMDx-Liver) for rejection, we now developed a parallel MMDx to characterize liver injury phenotypes. Methods: We used gene expression microarrays to study 337 liver transplant biopsies from 13 international centers, compared to clinical and histologic data collected as standard of care. Biopsies were characterized by their individual expression of injury-related gene sets: injury/repair (IRITs, IRRATs), macrophages (AMATs, QCMATs), acute stress (DAMPs), and immunoglobulins (IGTs). Unsupervised machine learning (principal component analysis-PCA, archetypal analysis-AA,) assigned each biopsy a set of injury-related PCA scores and AA scores (denoted by "I"). Results: PC1 was positively correlated with severely injured tissue, innate immune cell infiltration, wound repair/tissue remodeling, and histologic inflammation. PC2 strongly correlated with IGTs and time post-transplant, and anticorrelated with DAMPs. PC3 distinguished biopsies lacking in macrophages. PC1 correlated with histologic acute rejection and autoimmune hepatitis and PC2 with fibrosis. Unexpectedly, injury PC3 significantly correlated with steatohepatitis (p=8x10-4). Biopsies were assigned to groups by highest injury AA score: I1normal N=149, I2early N=36, I3severe N=17, and I4late N=135. The I1normal score described relatively normal biopsies. I2early described early injury, while I3injury related to tissue repair/remodeling (fibrillar collagens, IRITs). I4late described late biopsies with IGTs and not DAMPs, a phenomenon also observed in late kidney transplants with atrophyfibrosis. I4late, PC2, and to a lesser extent I3severe correlated with histologic fibrosis. Bilirubin, AST, ALT, and ALP increased with PC1, while albumin decreased. Albumin increased over time in I1normal and I2early, and decreased in I3severe and I4late. Conclusions: MMDx-Liver reveals four distinct groups characterized by their relationships to previously annotated injury features, potentially providing molecular definitions of steatohepatitis and the fibrosis/cirrhosis phenotypes.

PubMed ID

Not assigned.





First Page


Last Page