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World J Hepatol. Apr 27, 2014; 6(4): 217-225
Published online Apr 27, 2014. doi: 10.4254/wjh.v6.i4.217
Pediatric non-alcoholic fatty liver disease: New insights and future directions
Pierluigi Marzuillo, Emanuele Miraglia del Giudice, Nicola Santoro
Pierluigi Marzuillo, Emanuele Miraglia del Giudice, Department of women and children and General and Specialized Surgery, Seconda Università degli Studi di Napoli, 80138 Naples, Italy
Nicola Santoro, Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520, United States
Author contributions: All the authors conceived and wrote the manuscript.
Supported by The American Heart Association (AHA), No. 13SDG14640038; 2012 Yale Center for Clinical Investigation (YCCI) scholar award to Santoro N; CTSA Grant Number UL1 RR024139 from the National Center for Advancing Translational Science (NCATS), a component of the National Institutes of Health (NIH), and NIH roadmap for Medical Research
Correspondence to: Nicola Santoro, MD, PhD, Department of Pediatrics, Yale University School of Medicine, 330 Cedar Street, P.O. Box 208064, New Haven, CT 06520, United States.
Telephone: +1-203-7376356 Fax: +1-203-7856421
Received: October 17, 2013
Revised: February 25, 2014
Accepted: March 17, 2014
Published online: April 27, 2014

One of the most common complications of childhood obesity is the non-alcoholic fatty liver disease (NAFLD), which is the most common form of liver disease in children. NAFLD is defined by hepatic fat infiltration > 5% hepatocytes, as assessed by liver biopsy, in the absence of excessive alcohol intake, viral, autoimmune and drug-induced liver disease. It encompasses a wide spectrum of liver diseases ranging from simple steatosis to non-alcoholic steatohepatitis, which, in turn, can evolve into cirrhosis and end stage liver disease. Obesity and insulin resistance are the main risk factors for pediatric NAFLD. In fact, NAFLD is strongly associated with the clinical features of insulin resistance especially the metabolic syndrome, prediabetes and type 2 diabetes mellitus (T2D). In particular, it has been clearly shown in obese youth that the prevalence of metabolic syndrome, pre-diabetes and type 2 diabetes increases with NAFLD severity progression. Evidence that not all of the obese patients develop NAFLD suggests that the disease progression is likely to depend on complex interplay between environmental factors and genetic predisposition. Recently, a non-synonymous SNP (rs738409), characterized by a C to G substitution encoding an isoleucine to methionine substitution at the amino acid position 148 in the patatin like phospholipase containing domain 3 gene (PNPLA3), has been associated with hepatic steatosis in a multiethnic cohort of adults as well as in children. Another important polymorphisms that acts with PNPLA3 to convey susceptibility to fatty liver in obese youths is the rs1260326 polymorphism in the glucokinase regulatory protein. The pharmacological approach in NAFLD children poorly adherent to or being unresponsive/partially responsive to lifestyle changes, is aimed at acting upon specific targets involved in the pathogenesis. There are some therapeutic approaches that are being studied in children. This article reviews the current knowledge regarding the pediatric fatty liver disease, the new insights and the future directions.

Keywords: Non alcoholic fatty liver disease, PNPLA3, Obesity, Insulin resistance, Glucokinase regulatory protein, Fructose

Core tip: The prevalence of hepatic steatosis is increased in the last three decades concomitantly with the increased prevalence of pediatric obesity. Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease in children. The PNPLA3 rs738409 and the glucokinase regulatory protein rs1260326 are the strongest variants associated with fatty liver in paediatrics. Important risk factors are obesity, insulin resistence, gender, ethnicity and excessive dietetic intake of n-6 polyunsatured fatty acids and fructose. New pharmacological approaches are object of study, in NAFLD children poorly adherent to or being unresponsive/partially responsive to lifestyle changes.