Graduation Date

Fall 12-17-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Medical Sciences Interdepartmental Area

First Advisor

Teri J. Mauch, M.D., Ph.D.

Second Advisor

Carol Casey, Ph.D.

Third Advisor

Chi Lin, M.D., Ph.D.

Fourth Advisor

Babu Padanilam, Ph.D. and Christopher Wichman, Ph.D.

MeSH Headings

liver fibrosis, liver transplantation, elastography, biomarkers

Abstract

Hepatic graft fibrosis is a common histologic finding following pediatric liver transplant (LT) that may affect the long-term graft outcome. Hence, it is essential to identify hepatic graft fibrosis at a stage where fibrosis is not yet clinically apparent but has the potential for progression to initiate appropriate intervention and prevent its progression. Liver biopsy is the gold standard for fibrosis staging, but it is invasive, requires general anesthesia in children, and has potential complications. Our long-term goal is to implement non-invasive tests to assess and monitor the progression of hepatic graft fibrosis in liver-inclusive transplant children. The work presented in this dissertation is the initial step to achieving this goal. We aimed to (1) understand the prevalence of and potential risk factors for hepatic graft fibrosis in combined liver-small bowel transplant (LSBT) compared to LT children, and (2) investigate the diagnostic performance of the newer elastography technique 2D-shear wave elastography (2D-SWE) and selected serum markers for assessing hepatic graft fibrosis. We demonstrated that LSBT children could also develop hepatic graft fibrosis; its prevalence did not significantly differ from LT children (70.2% vs. 81.6%, p=0.19), but the predictors differed. Our scoping review of the limited number of available studies examining the usefulness of non-invasive tests for assessing hepatic graft fibrosis in LT children suggested that transient elastography in the pediatric LT setting had similar diagnostic value and limitations as in the non-transplant setting and current serum markers had unsatisfactory diagnostic accuracy. In the work presented here, we demonstrated that serum markers AST-to-platelet ratio index and Fibrosis-4 score (FIB4), especially graft FIB4 (calculated based on the hepatic graft's age), can accurately predict significant hepatic graft fibrosis in our LT/LSBT cohort; 2D-SWE had good diagnostic performance and may serve as a valuable adjunct tool for detecting significant hepatic graft fibrosis, especially when combined with these serum markers. We also reviewed the role of serum micro-RNA in the pathogenesis of hepatic fibrosis and its diagnostic application as potential novel biomarkers for the detection of hepatic graft fibrosis in the future.

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