Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 28, 2016; 22(36): 8078-8093
Published online Sep 28, 2016. doi: 10.3748/wjg.v22.i36.8078
Pediatric non-alcoholic fatty liver disease: Recent solutions, unresolved issues, and future research directions
Maria Grazia Clemente, Claudia Mandato, Marco Poeta, Pietro Vajro
Maria Grazia Clemente, Pediatric Clinic, Department of Surgical, Microsurgical and Medical Sciences, University of Sassari, 07100 Sassari, Italy
Claudia Mandato, Pediatrics of AORN Santobono-Pausilipon, 80123 Naples, Italy
Marco Poeta, Pietro Vajro, Pediatrics, Department of Medicine, Surgery and Dentistry - “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy
Pietro Vajro, ELFID European Laboratory for the Investigation of Food Induced Disease, 80138 Naples, Italy
Author contributions: Clemente MG and Mandato C contributed equally; Clemente MG, Mandato C and Vajro P reviewed the literature of NAFLD therapy, diagnosis and pathogenesis, respectively; Poeta M assembled references, figures and tables; all participated to writing the paper; Vajro P reviewed the final version which was agreed by everyone.
Conflict-of-interest statement: The authors declare there are no conflicts of interest in the content of this review.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Pietro Vajro, MD, Professor, Chair of Pediatrics, Pediatrics, Department of Medicine, Surgery and Dentistry - “Scuola Medica Salernitana”, University of Salerno, via Allende, 84081 Baronissi, Italy.
Telephone: +39-339-2361008 Fax: +39-089-672409
Received: June 30, 2013
Peer-review started: July 1, 2016
First decision: July 29, 2016
Revised: August 4, 2016
Accepted: August 23, 2016
Article in press: August 23, 2016
Published online: September 28, 2016

Non-alcoholic fatty liver disease (NAFLD) in children is becoming a major health concern. A “multiple-hit” pathogenetic model has been suggested to explain the progressive liver damage that occurs among children with NAFLD. In addition to the accumulation of fat in the liver, insulin resistance (IR) and oxidative stress due to genetic/epigenetic background, unfavorable lifestyles, gut microbiota and gut-liver axis dysfunction, and perturbations of trace element homeostasis have been shown to be critical for disease progression and the development of more severe inflammatory and fibrotic stages [non-alcoholic steatohepatitis (NASH)]. Simple clinical and laboratory parameters, such as age, history, anthropometrical data (BMI and waist circumference percentiles), blood pressure, surrogate clinical markers of IR (acanthosis nigricans), abdominal ultrasounds, and serum transaminases, lipids and glucose/insulin profiles, allow a clinician to identify children with obesity and obesity-related conditions, including NAFLD and cardiovascular and metabolic risks. A liver biopsy (the “imperfect” gold standard) is required for a definitive NAFLD/NASH diagnosis, particularly to exclude other treatable conditions or when advanced liver disease is expected on clinical and laboratory grounds and preferably prior to any controlled trial of pharmacological/surgical treatments. However, a biopsy clearly cannot represent a screening procedure. Advancements in diagnostic serum and imaging tools, especially for the non-invasive differentiation between NAFLD and NASH, have shown promising results, e.g., magnetic resonance elastography. Weight loss and physical activity should be the first option of intervention. Effective pharmacological treatments are still under development; however, drugs targeting IR, oxidative stress, proinflammatory pathways, dyslipidemia, gut microbiota and gut liver axis dysfunction are an option for patients who are unable to comply with the recommended lifestyle changes. When morbid obesity prevails, bariatric surgery should be considered.

Keywords: Non-alcoholic fatty liver disease, Childhood obesity, Non-alcoholic steatohepatitis, Hepatic metabolic syndrome, Non-alcoholic fatty liver disease diagnosis

Core tip: Due to the high prevalence of obesity worldwide, non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, represents the most common chronic liver disease in children living in industrialized countries. The present review summarizes the currently available knowledge on NAFLD pathogenesis, diagnosis and treatment, highlights new research achievements that will likely influence therapeutic strategies and discusses possible future directions in pediatric research.