Identification of Reliable Biomarkers for the Progression of Non-Alcoholic Fatty Liver Disease in Obese Pediatric Patients
80% of morbidly obese adolescents suffer from on-alcoholic fatty liver disease (NAFLD), giving an urgent need for reliable and feasible markers to screen for fatty liver and fibrosis in children and adolescents. Since biopsy is still the gold standard in diagnosis of NAFLD, a more feasible noninvasive screening tool is sought, especially for the high risk group of morbidly obese children and adolescents. Therefore, this study aims at identifying biomarkers in blood, which might offer reliable information on the presence and progression of NAFLD in obese children and adolescents. NAFLD has been shown to be associated withaltered DNA methylation in liver correlating with changes in gene expression and an altered miRNA profile. Hence, potential circulating epigenetic predictors for NAFLD and/or NASH and hepatic fibrosis published for adult patients will be tested in obese children and adolescents.
Aim of the study:
It is evident that for pediatric patients therapeutic intervention regarding the progression of hepatic steatosis to NASH independent of lifestyle modifications is highly desirable. Improvements are currently limited by a lack of optimal methods to screen for children at risk and a still limited knowledge on the pathogenic mechanisms driving progression of NAFLD. Therefore, this study aims at identifying epigenetic biomarkers in serum, which offer reliable information on the presence and progression of NAFLD in obese children and adolescents. To achieve this aim, this study will follow three strategies to be tested in obese children and adolescents that will be grouped into patients with no NAFLD, simple steatosis, and progressed NAFLD by MRI and published serum markers:
1. Potential circulating epigenetic predictors for NAFLD and/or NASH and hepatic fibrosis published for adult patients will be tested in obese children and adolescents.This part refers in particular to extracellular miRNAs.
2. To test whether the shown methylation pattern differences associated with NAFLD and hepatic fibrosis in liver are reflected in changes in blood of obese pediatric patients. For this goal, we will focus on genes that are known to be also expressed in blood and, ideally, have a function related to inflammation and oxidative stress, as, for instance, AHR (Aryl-hyrdocarbon receptor).
3. To directly focus on methylation of genes involved inflammation and oxidative stress, which represent main factors in driving NAFLD progression. For this aim we can refer to preliminary data of the lab, which show an association of methylation of a distinct site in the TNFα promoter with liver steatosis.
Methods and Skills:
Clinical studies; bisulfite sequencing; microRNA quantification; epigenetics
Item CB, Schanzer A, Metz T, Greber-Platzer S, Lischka J. Demethylation of the hypoxia induction factor 1 binding site of GPX3 at excess blood ammonia in propionic acidemia. Clin Biochem 66: 100-102, 2019
Lischka, J, Schanzer, A, Hojreh, A, et al. A branched‐chain amino acid‐based metabolic score can predict liver fat in children and adolescents with severe obesity. Pediatric Obesity 2020; e12739. doi: 10.1111/ijpo.12739. Online ahead of print.