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Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in childhood/adolescence. It comprises a broad spectrum of liver disease severity ranging from simple steatosis to steatohepatitis and fibrosis. To date lifestyle modifications, diet and physical activity represent the main option for the management of pediatric NAFLD, but numerous treatments classified depending on the mechanism of action, have been introduced. In keeping with, bariatric surgery, insulin sensitizers, antioxidants, probiotic and dietary supplementations have been evaluated in pediatric clinical trials. This review describes, after a search in PubMed/MEDLINE database, the current pediatric NAFLD non-pharmacological and pharmacological treatments and their effects on biochemical and histological features. We report not only the efficacy of the diet coupled with regular exercise but also advantages of the pharmacological treatments used in combination with lifestyle interventions in pediatric NAFLD. Since pharmacological and non-pharmacological interventions have demonstrated variable effects in pediatric NAFLD, it is clear that safe and specific and efficient therapeutic strategies have not yet been identified. Therefore, large and long-term clinical trials in children are needed to find a way to reverse the liver tissue damage and the NAFLD-related long-term morbidity and mortality. [ABSTRACT FROM AUTHOR]

Atypical fibroblast growth factors (FGF) 21 and 19 play a central role in energy metabolism through the mediation of Klotho coreceptor. Contradictory findings are available about the association of FGF21 and FGF19 with nonalcoholic fatty liver disease (NAFLD) in humans. We investigated the association of serum FGF21, FGF19 and liver Klotho coreceptor with non-alcoholic steatohepatitis (NASH) and fibrosis in children with NAFLD. Serum FGF21 and FGF19 were measured in 84 children with biopsy-proven NAFLD and 23 controls (CTRL). The hepatic expression of Klotho coreceptor was measured in 7 CTRL, 9 patients with NASH (NASH+) and 11 patients without NASH (NASH−). FGF21 and FGF19 showed a tendency to decrease from CTRL (median FGF21 = 196 pg/mL; median FGF19 = 201 pg/mL) to NASH− (FGF21 = 89 pg/mL; FGF19 = 81 pg/mL) to NASH+ patients (FGF21 = 54 pg/mL; FGF19 = 41 pg/mL) (p<0.001 for all comparisons) and were inversely associated with the probability of NASH and fibrosis in children with NAFLD. The hepatic expression of Klotho coreceptor was inversely associated with NASH (R2 = 0.87, p<0.0001) and directly associated with serum FGF21 (R2 = 0.57, p<0.0001) and FGF19 (R2 = 0.67, p<0.0001). In conclusion, serum FGF19 and FGF21 and hepatic Klotho expression are inversely associated with hepatic damage in children with NAFLD and these findings may have important implications for understanding the mechanisms of NAFLD progression. [ABSTRACT FROM AUTHOR]

Intrauterine growth retardation (IUGR), the most important cause of perinatal mortality and morbidity, is defined as a foetal growth less than normal for the population, often used as synonym of small for gestational age (SGA). Studies demonstrated the relationships between metabolic syndrome (MS) and birthweight. This study suggested that, in children, adolescents, and adults born SGA, insulin resistance could lead to other metabolic disorders: type 2 diabetes (DM2), dyslipidemia, and nonalcoholic fatty liver disease (NAFLD). NAFLD may evolve to nonalcoholic steatohepatitis (NASH), and it is related to the development of MS. Lifestyle intervention, physical activity, and weight reduction represent the mainstay of NAFLD therapy. In particular, a catch-up growth reduction could decrease the risk to develop MS and NAFLD. In this paper, we outline clinical and experimental evidences of the association between IUGR, metabolic syndrome, insulin resistance, and NAFLD and discuss on a possible management to avoid the risk of MS in adulthood. [ABSTRACT FROM AUTHOR]

• The KLB rs17618244 variant increases the risk of ballooning and lobular inflammation in children with NAFLD. • KLB plasma levels are lower in carriers of the rs17618244 minor A allele. • KLB plasma levels are associated with lobular inflammation, ballooning and fibrosis. • KLB mutant induces intracellular lipid accumulation in HepG2 and Huh7. • KLB mutant causes upregulation of lipotoxic and proinflammatory genes. Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in adults and children. Along with obesity, diabetes and insulin resistance, genetic factors strongly impact on NAFLD development and progression. Dysregulated bile acid metabolism and the fibroblast growth factor 19 (FGF19) pathway play a pivotal role in NAFLD pathogenesis. However, the mechanism through which the FGF19 receptor system is associated with liver damage in NAFLD remains to be defined. We evaluated the impact of the rs17618244 G>A β-Klotho (KLB) variant on liver damage in 249 pediatric patients with biopsy-proven NAFLD and the association of this variant with the expression of hepatic and soluble KLB. In vitro models were established to investigate the role of the KLB mutant. The KLB rs17618244 variant was associated with an increased risk of ballooning and lobular inflammation. KLB plasma levels were lower in carriers of the rs17618244 minor A allele and were associated with lobular inflammation, ballooning and fibrosis. In HepG2 and Huh7 hepatoma cell lines, exposure to free fatty acids caused a severe reduction of intracellular and secreted KLB. Finally, KLB downregulation obtained by the expression of a KLB mutant in HepG2 and Huh7 cells induced intracellular lipid accumulation and upregulation of p62, ACOX1, ACSL1, IL-1β and TNF-α gene expression. In conclusion, we showed an association between the rs17618244 KLB variant, which leads to reduced KLB expression, and the severity of NAFLD in pediatric patients. We can speculate that the KLB protein may exert a protective role against lipotoxicity and inflammation in hepatocytes. Genetic and environmental factors strongly impact on the pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD). The FGF19/FGFR4/KLB pathway plays a pivotal role in the pathogenesis of NAFLD. The aim of the study was to investigate the impact of a genetic variant in the KLB gene on the severity of liver disease. Our data suggest that the KLB protein plays a protective role against lipotoxicity and inflammation in hepatocytes. [ABSTRACT FROM AUTHOR]