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Title: Histopathological aspects of idiopathic chronic hepatitis and antibody-mediated injury to the liver allograft
Author: Neves Souza, Lara
ISNI:       0000 0004 7970 0332
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2019
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Background and aim: Histological abnormalities in protocol biopsies of liver allografts are common, particularly idiopathic post-transplant chronic hepatitis (IPTH) and fibrosis. Recently, emerging evidence suggests that antibody-mediated rejection (AMR) might play a role in acute and chronic liver allograft injury, but this is not well defined as in other allograft organs. This research consisted of a histopathological study of liver allografts, with emphasis on IPTH and AMR. The aim was to investigate IPTH as a cause of allograft loss, and to correlate histological findings of post-transplant biopsies, including IPTH, fibrosis and specific cell phenotypes, with signs of AMR and with gene expression profile. Methodology: Three cohorts corresponding to three distinct post-transplantation settings were analysed: failed allografts removed at retransplantation, long-term protocol biopsies of clinically asymptomatic liver recipients, and for cause biopsies with a diagnosis of cellular/T-cell mediated rejection (TCMR). Several parameters of allograft injury were scored by two pathologists on HE and reticulin stained slides. Fibrosis was digitally measured in Sirius Red slides (collagen proportionate area). Multiplex immunostaining with quantum dots and fluorescent dyes was performed and digital image analysis was conducted to quantify B cells, plasma cells and T cells and their subtypes. RNA was extracted from biopsies and analysed with RNA sequencing, and the results compared to gene signatures of known liver pathologies. Results: A steady increase in IPTH leading to allograft loss was observed, and this was the main reason for retransplantation conducted >10 years after primary transplantation in children 6 in the most recent era. The protocol biopsies of 73% of children were abnormal, and IPTH associated with fibrosis was the most common finding. Donor-specific antibodies (DSA) were present in 69% of recipients, mainly class II DSA, and were associated with lobular inflammation. Portal microvascular C4d positivity (C4d+) was linked to a humoral inflammatory cell profile (B cells and plasma cells), central perivenulitis, lobular inflammation, and each sinusoidal and centrilobular fibrosis. The combination of DSA+C4d+ was also associated with central perivenulitis and sinusoidal fibrosis, and additionally, to interface activity. B cells and plasma cells were linked to fibrosis in all compartments. In biopsies with rejection, portal microvascular C4d+ was a specific and sensitive indicator of DSA II. Bile duct loss in this group was strongly linked to DSA, and portal fibrosis to DSA+C4d+. Considering current Banff criteria for AMR, 12% of patients in the protocol biopsy group, and a fourth of patients in the rejection cohort had a diagnosis of chronic and acute AMR established, respectively. Gene expression profiles were not significantly different between patients with and without DSA. Conclusion: IPTH can slowly evolve to allograft failure. The associations found in both biopsy cohorts (protocol and rejection) between fibrosis and DSA+C4d+ (and a humoral inflammatory profile in protocol biopsies) suggest that unexplained fibrosis in both settings is likely connected to AMR. In longterm post-transplant biopsies of asymptomatic children, unexplained inflammation, especially interface activity, central perivenulitis and lobular inflammation (even mild), also seem to represent chronic ongoing AMR. When diagnosis of TCMR is established, the possibility of concurrent AMR should be carefully considered, and the finding of bile duct loss should be regarded as a potential sign of AMR. Gene signatures of AMR could not be found. This highlights the importance of histological assessment in monitoring allograft health, even when patients are clinically asymptomatic with normal liver function tests.
Supervisor: Sanchez Fueyo, Alberto Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available