Progressive Fibrosis is Driven by Genetic Predisposition, Allo-Immunity, and Inflammation in Pediatric Liver Transplant Recipients

Varma, Sharat; Ambroise, Jérôme; Komuta, Mina; Latinne, Dominique; Baldin, Paméla; Reding, Raymond; Smets, Françoise; Stéphenne, Xavier; Sokal, Étienne

doi:10.1016/j.jceh.2016.06.064

Cited by 7 publications

(13 citation statements)

References 19 publications

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“…The importance of protocol biopsy and their interpretation was recently studied using successive protocol biopsies from stable pediatric LT recipients. It was observed that allograft inflammation preceded fibrosis and the severity of inflammation was related the magnitude of the consequent fibrosis . This study establishes the link between the allograft inflammation and fibrosis and probably opens up an avenue for intervention.…”

Section: Discussionsupporting

confidence: 59%

“…Increased long‐term survival has however revealed increasing graft fibrosis and other histological changes which progressively increase over time following LT . The factors involved in late allograft fibrosis and potential treatments that can reverse or delay its development are a subject of current research . To monitor allograft health and treatment efficacy, finding an efficient predictive marker of fibrosis development proves to be a top priority.…”

Section: Introductionmentioning

confidence: 99%

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The histological quantification of alpha‐smooth muscle actin predicts future graft fibrosis in pediatric liver transplant recipients

Varma

Stéphenne

Komuta

et al. 2016

Pediatric Transplantation

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Activated hepatic stellate cells express cytoplasmic ASMA prior to secreting collagen and consequent liver fibrosis. We hypothesized that quantifying ASMA could predict severity of future fibrosis after LT. For this, 32 pairs of protocol biopsies, that is, "baseline" and "follow-up" biopsies taken at 1- to 2-year intervals from 18 stable pediatric LT recipients, transplanted between 2006 and 2012 were selected. Morphometric quantification of "ASMA-positive area percentage" was performed on the baseline biopsy. Histological and fibrosis assessment using Metavir and LAFSc was performed on all biopsies. The difference of fibrosis severity between the "baseline" and "follow-up" was termed "prospective change in fibrosis." Significant association was seen between extent of ASMA positivity on baseline biopsy and "prospective change in fibrosis" using Metavir (P=.02), cumulative LAFSc (P=.02), and portal LAFSc (P=.01) values. ASMA-positive area percentage >1.05 predicted increased fibrosis on next biopsy with 90.0% specificity. Additionally, an association was observed between extent of ASMA positivity and concomitant ductular reaction (P=.06), but not with histological inflammation in the portal tract or lobular area. Hence, ASMA quantification can predict the future course of fibrosis.

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Section: Discussionsupporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

The histological quantification of alpha‐smooth muscle actin predicts future graft fibrosis in pediatric liver transplant recipients

Varma

Stéphenne

Komuta

et al. 2016

Pediatric Transplantation

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“…The random slope, 1 þ testjcase ð Þ , accounts for memorization between successive tests of real stages given repeated measurements per case. Virtual stage was modeled from these predictors using ordinal logistic regression with a cumulative link model, which assumes that fibrosis stages represent the space between "cut points" in a latent distribution of the true underlying continuous fibrosis progression [59][60][61]. To handle uncertainty in pathologist assigned stage (521 observations, or 15% of the dataset featured reported interval measurements to convey uncertainty, e.g., F2-F3; impacts 67% of the slides), we separately considered the upper bound (e.g., F3) and the lower bound (e.g., F2) of the measurement interval.…”

Section: Quantitative Assessment Of Concordancementioning

confidence: 99%

A large-scale internal validation study of unsupervised virtual trichrome staining technologies on nonalcoholic steatohepatitis liver biopsies

et al. 2021

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Non-alcoholic steatohepatitis (NASH) is a fatty liver disease characterized by accumulation of fat in hepatocytes with concurrent inflammation and is associated with morbidity, cirrhosis and liver failure. After extraction of a liver core biopsy, tissue sections are stained with hematoxylin and eosin (H&E) to grade NASH activity, and stained with trichrome to stage fibrosis. Methods to computationally transform one stain into another on digital whole slide images (WSI) can lessen the need for additional physical staining besides H&E, reducing personnel, equipment, and time costs. Generative adversarial networks (GAN) have shown promise for virtual staining of tissue. We conducted a large-scale validation study of the viability of GANs for H&E to trichrome conversion on WSI (n = 574). Pathologists were largely unable to distinguish real images from virtual/synthetic images given a set of twelve Turing Tests. We report high correlation between staging of real and virtual stains ($${\rho} = 0.86$$ ρ = 0.86 ; 95% CI: 0.84–0.88). Stages assigned to both virtual and real stains correlated similarly with a number of clinical biomarkers and progression to End Stage Liver Disease (Hazard Ratio HR = 2.06, 95% CI: 1.36–3.12, p < 0.001 for real stains; HR = 2.02, 95% CI: 1.40–2.92, p < 0.001 for virtual stains). Our results demonstrate that virtual trichrome technologies may offer a software solution that can be employed in the clinical setting as a diagnostic decision aid.

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“…have suggested that the prevalence of graft hepatitis and fibrosis increases with time (24), although at the time of print there is new evidence of the contrary (25), and that late pediatric graft fibrosis without inflammation may be related to low-grade AMR (26). The panel debate pro-and contra-protocol biopsies raised the following points:…”

Section:  Role Of Protocol Liver Biopsymentioning

confidence: 99%

“…The arguments for protocol biopsies: DSA may influence the graft in more subtle ways. De-novo DSA are now accepted to be implicated in adverse outcomes including the chronic histopathological changes appreciated on long-term biopsies (25,27). In the few pediatric studies to date, DSA/C4d assessment suggests that humoral immunity may be a player in "idiopathic" late graft fibrosis (26) protocols.…”

Section:  Role Of Protocol Liver Biopsymentioning

confidence: 99%

Early and Late Factors Impacting Patient and Graft Outcome in Pediatric Liver Transplantation

Mclin¹,

Allen

Boyer

et al. 2017

J. pediatr. gastroenterol. nutr.

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As pediatric liver transplantation comes of age, experts gathered to discuss current paradigms and define gaps in knowledge warranting research to further improve patient and graft outcomes. Identified areas ripe for collaborative research include understanding the molecular and cellular mechanisms of tolerance and the role of donor-specific antibodies, considering ways to expand donor pool, minimizing long-term side effects of immunosuppression, and fine-tuning surgical techniques to minimize biliary and vascular complications.

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Progressive Fibrosis is Driven by Genetic Predisposition, Allo-Immunity, and Inflammation in Pediatric Liver Transplant Recipients

Cited by 7 publications

References 19 publications

The histological quantification of alpha‐smooth muscle actin predicts future graft fibrosis in pediatric liver transplant recipients

The histological quantification of alpha‐smooth muscle actin predicts future graft fibrosis in pediatric liver transplant recipients

A large-scale internal validation study of unsupervised virtual trichrome staining technologies on nonalcoholic steatohepatitis liver biopsies

Early and Late Factors Impacting Patient and Graft Outcome in Pediatric Liver Transplantation

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