Identification of sociodemographic, biochemical and epigenetic biomarkers of hepatic steatosis in children with overweight or obesity

Abstract

Childhood obesity is one of the 21st century's most serious public health challenges, becoming in the most prevalent cardiometabolic disease. In the last two decades, in parallel with the childhood obesity epidemic, several associated comorbidities such as cardiovascular diseases, type 2 diabetes (T2D) and metabolic associated fatty liver disease (MAFLD) have raised in paediatric population. MAFLD has emerged as one of the most serious comorbidities of childhood obesity, and the most common cause of chronic liver disease among children and young adults worldwide. MAFLD encompasses a spectrum of diseases ranging from steatosis to steatohepatitis, fibrosis and eventually cirrhosis, worsening and complicating the stage and the reversibility of the disease. The asymptomatic evolution of MAFLD, together with its high prevalence and costly and/or invasive diagnosis methods (liver biopsy and/or magnetic resonance imaging) make difficult the early identification of children with the disease. Paediatric MAFLD development and progression mechanisms are complex and multifactorial. Specific genetic polymorphisms and epigenetic modifications, sociodemographic and lifestyle factors have been associated with the development of the disease. The identification of risk factors for paediatric MAFLD development and the study of potential biomarkers for its diagnosis is crucial for its early prevention and treatment. Thus, there is agreement among scientific/medical associations on the need to develop useful screening tools to detect paediatric MAFLD. Therefore, the overall objectives of the present International Doctoral Thesis were: i) to develop a minimally invasive screening protocol with high predictive potential for the identification of children with overweight or obesity candidates to confirmatory diagnosis of MAFLD that can be useful in clinical practice ii) to systematically analyse the biomarker role of circulating miRNAs in the early onset of obesity and obesity associated co-morbidities through the examination of available circulating miRNA profile data in children and adolescents with obesity, and in obesity-associated metabolic abnormalities, and iii) to identify potential miRNA biomarkers of early MAFLD and/or IR in preadolescent children, and to test their associations with cardiometabolic risk factors. In order to achieve these objectives, data from the EFIGRO, PREDIKID and MICROKID investigation projects were considered. The conclusions from the current Thesis are: i) sociodemographic and lifestyle factors such as ethnic minority, prematurity at birth, elevated waist to height circumference ratio, sugar sweetened consumption, screen time and low cardiorespiratory fitness are consistently associated with the presence of hepatic steatosis in children with overweight or obesity, ii) at present, available screening methods for MAFLD identification in children have limited accuracy and applicability, iii) the HEPAKID index pre-screening tool is the first sociodemographic, lifestyle and anthropometric data-based screening method for identifying children with overweight or obesity whit elevated risk to suffer hepatic steatosis, iv) biochemical parameters such as, plasma TG, insulin, HOMA-IR, AST, ALT, GGT and ferritin levels, as well as the presence of risk alleles of PPARGrs13081389, PPARGrs1801282, HFErs1800562 and PNLPLA3rs4823173 polymorphisms, are consistently associated with the presence of hepatic steatosis in children with overweight or obesity. However, their prediction capacity is not enough for the screening of MAFLD, v) the HEPAKID prediction protocol identifies with high sensitivity, specificity and accuracy, as well as low time-consuming and economic cost, children with overweight or obesity who likely suffer from MAFLD, and who should be referred for confirmatory diagnosis, vi) circulating miRNAs could be promising diagnostic biomarkers of obesity-associated diseases, such as MAFLD and T2D, already in childhood. However, it was not possible to identify a concrete miRNA profile in children with obesity in the literature, vii) circulating miR-660-5p seems to be a biomarker of the presence of MAFLD in preadolescent children, regardless of weight status, and viii) circulating miR-320a, miR-142-3p, miR-190a-5p, miR-374a-5p and let-7 family miRNAs could serve as potential biomarkers of IR in children.