Pediatric metabolic (dysfunction)-associated fatty liver disease: current insights and future perspectives

Abstract

The historical use of the term non-alcoholic fatty liver disease (NAFLD) in obese/overweight children has been controversial as to the appropriateness of this terminology in children, and lately, in adults too. Newer game-changer terminology, metabolic (dysfunction)-associated fatty liver disease (MAFLD), for this condition signifies a positive step forward that addresses the limitations of the previous definition for both adults and children. The prevalence of MAFLD has surged in tandem with the global rise in obesity rates, establishing itself as a predominant cause of chronic liver disease in both adult and pediatric populations. The adoption of the recently proposed nomenclature reflects a more encompassing comprehension of the disease and its etiology compared to its predecessor, NAFLD. Notably, the revised terminology facilitates the recognition of MAFLD as an autonomous condition while acknowledging the potential coexistence of other systemic fatty liver disorders. Particularly in children, this includes various paediatric-onset genetic and inherited metabolic disorders, necessitating thorough exclusion, especially in cases where weight loss interventions yield no improvement or in the absence of obesity. MAFLD presents as a multifaceted disorder; evidence suggests its origins lie in a complex interplay of nutritional, genetic, hormonal, and environmental factors. Despite advancements, current non-invasive diagnostic biomarkers exhibit limitations in accuracy, often necessitating imaging and histological evaluations for definitive diagnosis. While dietary and lifestyle modifications stand as cornerstone measures for MAFLD prevention and management, ongoing evaluation of therapeutic agents continues. This article provides an overview of the latest developments and emerging therapies in the realm of paediatric MAFLD.

Keywords: Adolescents; Children; Diet; Fatty liver disease; Gut microbiome; Lifestyle; Metabolic (dysfunction)-associated fatty liver disease (MAFLD); Non-alcoholic fatty liver disease (NAFLD); Nutrition; Obesity; Weight loss.

Fig. 1

Proposed diagnostic criteria (Modified from Ref. #4 Eslam et al, Lancet Gastroenterol Hepatol 2021)

Fig. 2

Diets high in saturated fats, sucrose and fructose are steatogenic and cause dysregulation of key lipid metabolic pathways and hormones. The development of insulin resistance in MAFLD leads to increased adipocyte lipolysis and high circulating free fatty acids available for subsequent hepatic uptake. This leads to intrahepatic lipid accumulation. In hepatocytes, the inability to accommodate neutral lipids within lipid droplets exposes cells to lipotoxic bioactive lipids. Lipotoxicity causes oxidative damage and promotes inflammation and fibrosis through a number of mechanisms. (Created with Biorender)

Fig. 3

The intestinal barrier is composed of a mucus layer, intestinal epithelium, mucosal immune system, and gut vascular barrier. When its integrity is damaged by an abnormal GM composition (gut dysbiosis) there is an increased intestinal permeability leading to unrestrained transfer of noxious bacterial substances/metabolites (SCFA, ethanol, LPS) and various pro-inflammatory molecules to the liver through the portal system (Gut-Liver Axis). These events contribute to steatosis and accelerate inflammatory and fibrogenic progression of MAFLD. Moreover bile acids (BA) produced by hepatocytes are further metabolized by a dysbiotic GM and may result in an atypical primary/secondary BA pool (DCA > CDCA). This a) interferes with Tight Junctions, and b) binds atypically to the BA receptors (e.g. TGR5, FXR and VDR) along the enterohepatic system, resulting in carbohydrate and lipid metabolism dysfunction [1]. (Created with Biorender). GM Gut Microbiome, SCFA Short chain fatty acid, LPS lipopolysaccharide, BA Bile acids, DCA deoxycholic acid, CDCA chenodeoxycholic acid, TGR5 Takeda G protein receptor 5, FXR Farnesoid X receptor, VDR vitamin D receptor