Molecular profiling of subclinical inflammatory lesions in long-term surviving adult liver transplant recipients

• Published in: Journal of hepatology 2018-09, Vol.69 (3), p.626-634
• Main Authors: Londoño, María-Carlota, Souza, Lara Neves, Lozano, Juan-José, Miquel, Rosa, Abraldes, Juan G., Llovet, Laura-Patricia, Quaglia, Alberto, Rimola, Antoni, Navasa, Miquel, Sánchez-Fueyo, Alberto
• Format: Article
• Language: English
• Subjects: Adult; Adults; Allografts; Asymptomatic Diseases; Biopsy; Biopsy - methods; Correlation of Data; Disease Progression; Female; Fibrosis; Fibrosis - immunology; Fibrosis - pathology; Gene expression; Gene Expression Profiling - methods; Genomes; Graft rejection; Graft Rejection - etiology; Graft Rejection - pathology; Hepatitis; Hepatocytes; Histological abnormalities; Humans; Idiopathic hepatitis; Inflammation; Inflammation - immunology; Inflammation - pathology; Liver - immunology; Liver - pathology; Liver diseases; Liver Function Tests - methods; Liver transplant; Liver transplantation; Liver Transplantation - adverse effects; Liver Transplantation - methods; Long Term Adverse Effects - immunology; Long Term Adverse Effects - pathology; Long-term; Lymphocytes T; Male; Middle Aged; Next-generation sequencing; Ribonucleic acid; RNA; Serological tests; Subclinical inflammation; T cell mediated rejection; T-Lymphocytes - immunology; T-Lymphocytes - pathology; Transcription; Transplants & implants
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2018.04.012

[Display omitted] •Histological abnormalities are often observed in liver transplant recipients despite normal or near normal liver tests.•Recipients with portal inflammation have a liver tissue transcriptional profile resembling the T-cell mediated rejection.•Recipients with subclinical lesions and high expression of rejection-associated transcripts are at risk of progressive liver damage. Subclinical inflammatory changes are commonly described in long-term transplant recipients undergoing protocol liver biopsies. The pathogenesis of these lesions remains unclear. The aim of this study was to identify the key molecular pathways driving progressive subclinical inflammatory liver allograft damage. All liver recipients followed at Hospital Clínic Barcelona who were >10 years post-transplant were screened for participation in the study. Patients with recurrence of underlying liver disease, biliary or vascular complications, chronic rejection, and abnormal liver function tests were excluded. Sixty-seven patients agreed to participate and underwent blood and serological tests, transient elastography and a liver biopsy. Transcriptome profiling was performed on RNA extracted from 49 out of the 67 biopsies employing a whole genome next generation sequencing platform. Patients were followed for a median of 6.8 years following the index liver biopsy. Median time since transplantation to liver biopsy was 13 years (10–22). The most frequently observed histological abnormality was portal inflammation with different degrees of fibrosis, present in 45 biopsies (67%). Two modules of 102 and 425 co-expressed genes were significantly correlated with portal inflammation, interface hepatitis and portal fibrosis. These modules were enriched in molecular pathways known to be associated with T cell mediated rejection. Liver allografts showing the highest expression levels for the two modules recapitulated the transcriptional profile of biopsies with clinically apparent rejection and developed progressive damage over time, as assessed by non-invasive markers of fibrosis. A large proportion of adult liver transplant recipients who survive long-term exhibit subclinical histological abnormalities. The transcriptomic profile of these patients’ liver tissue closely resembles that of T cell mediated rejection and may result in progressive allograft damage. A large proportion of adult liver transplant recipients who survive for a long time exhibit subclinical histological abnormalities.