The molecular phenotypes of injury, steatohepatitis, and fibrosis in liver transplant biopsies in the INTERLIVER study

Katelynn S Madill-Thomsen, Marwan Abouljoud, Chandra Bhati, Michał Ciszek, Magdalena Durlik, Sandy Feng, Bartosz Foroncewicz, Iman Francis, Michał Grąt, Krzysztof Jurczyk, Goran Klintmalm, Maciej Krasnodębski, Geoff McCaughan, Rosa Miquel, Aldo Montano-Loza, Dilip Moonka, Krzysztof Mucha, Marek Myślak, Leszek Pączek, Agnieszka Perkowska-Ptasińska, Grzegorz Piecha, Trevor Reichman, Alberto Sanchez-Fueyo, Olga Tronina, Marta Wawrzynowicz-Syczewska, Andrzej Więcek, Krzysztof Zieniewicz, Philip F Halloran, Katelynn S Madill-Thomsen, Marwan Abouljoud, Chandra Bhati, Michał Ciszek, Magdalena Durlik, Sandy Feng, Bartosz Foroncewicz, Iman Francis, Michał Grąt, Krzysztof Jurczyk, Goran Klintmalm, Maciej Krasnodębski, Geoff McCaughan, Rosa Miquel, Aldo Montano-Loza, Dilip Moonka, Krzysztof Mucha, Marek Myślak, Leszek Pączek, Agnieszka Perkowska-Ptasińska, Grzegorz Piecha, Trevor Reichman, Alberto Sanchez-Fueyo, Olga Tronina, Marta Wawrzynowicz-Syczewska, Andrzej Więcek, Krzysztof Zieniewicz, Philip F Halloran

Abstract

To extend previous molecular analyses of rejection in liver transplant biopsies in the INTERLIVER study (ClinicalTrials.gov #NCT03193151), the present study aimed to define the gene expression selective for parenchymal injury, fibrosis, and steatohepatitis. We analyzed genome-wide microarray measurements from 337 liver transplant biopsies from 13 centers. We examined expression of genes previously annotated as increased in injury and fibrosis using principal component analysis (PCA). PC1 reflected parenchymal injury and related inflammation in the early posttransplant period, slowly regressing over many months. PC2 separated early injury from late fibrosis. Positive PC3 identified a distinct mildly inflamed state correlating with histologic steatohepatitis. Injury PCs correlated with liver function and histologic abnormalities. A classifier trained on histologic steatohepatitis predicted histologic steatohepatitis with cross-validated AUC = 0.83, and was associated with pathways reflecting metabolic abnormalities distinct from fibrosis. PC2 predicted histologic fibrosis (AUC = 0.80), as did a molecular fibrosis classifier (AUC = 0.74). The fibrosis classifier correlated with matrix remodeling pathways with minimal overlap with those selective for steatohepatitis, although some biopsies had both. Genome-wide assessment of liver transplant biopsies can not only detect molecular changes induced by rejection but also those correlating with parenchymal injury, steatohepatitis, and fibrosis, offering potential insights into disease mechanisms for primary diseases.

Keywords: basic (laboratory) research/science; biopsy; liver transplantation/hepatology; microarray/gene array; rejection.

© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.

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