ORIGINAL CONTRIBUTIONS: LIVERLow Birthweight Increases the Likelihood of Severe Steatosis in Pediatric Non-Alcoholic Fatty Liver DiseaseBugianesi, Elisabetta MD, PhD1,8; Bizzarri, Carla MD2,8; Rosso, Chiara PhD1; Mosca, Antonella MD3; Panera, Nadia PhD4; Veraldi, Silvio MD3; Dotta, Andrea MD5; Giannone, Germana MSc6; Raponi, Massimiliano MD7; Cappa, Marco MD2; Alisi, Anna PhD4,8; Nobili, Valerio MD3,8Author Information 1Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy 2Unit of Endocrinology and Diabetes, “Bambino Gesù” Children’s Hospital, IRCCS (Instituto di Ricovero e Cura a Carattere Scientifico), Rome, Italy 3Hepato-Metabolic Disease Unit, “Bambino Gesù” Children’s Hospital, IRCCS (Instituto di Ricovero e Cura a Carattere Scientifico), Rome, Italy 4Liver Reseach Unit, “Bambino Gesù” Children’s Hospital, IRCCS (Instituto di Ricovero e Cura a Carattere Scientifico), Rome, Italy 5Neonatal Surgery Unit, “Bambino Gesù” Children’s Hospital, IRCCS (Instituto di Ricovero e Cura a Carattere Scientifico), Rome, Italy 6Department of Laboratory Medicine, “Bambino Gesù” Children’s Hospital, IRCCS (Instituto di Ricovero e Cura a Carattere Scientifico), Rome, Italy 7Medical Directorate, “Bambino Gesù” Children’s Hospital, IRCCS (Instituto di Ricovero e Cura a Carattere Scientifico), Rome, Italy Correspondence: Valerio Nobili, MD, Hepato-Metabolic Disease Unit, “Bambino Gesù” Children’s Hospital, IRCCS (Instituto di Ricovero e Cura a Carattere Scientifico), P.le S. Onofrio, 4, Rome 00165, Italy. E-mail: firstname.lastname@example.org 8These authors contributed equally to this work SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/AJG/A534 Received 30 December 2016; accepted 03 April 2017 Guarantor of the article: Valerio Nobili, MD. Specific author contributions: Dr Bugianesi, Dr Bizzarri, Dr Cappa, Dr Alisi, and Dr Nobili conceptualized and designed the study, drafted the initial manuscript, and critically reviewed the manuscript. Dr Panera, Dr Dotta, and Dr Raponi performed assays, analyzed data and interpreted results, and drafted the initial manuscript. Dr Rosso, Dr Mosca, Dr Veraldi, and Dr Giannone enrolled patients, collected data, and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. Financial support: V.N. is supported by the Italian Ministry of Health funds (Fondi di Ricerca Corrente 2016). All authors have indicated they have no financial relationships relevant to this article to disclose. Potential competing interests: None. American Journal of Gastroenterology: August 2017 - Volume 112 - Issue 8 - p 1277-1286 doi: 10.1038/ajg.2017.140 Buy SDC Metrics Abstract Objectives: Small for gestational age (SGA) is associated with an increased risk of non-alcoholic fatty liver disease (NAFLD). Our aim was to investigate the correlation of birthweight with the severity of liver damage in a large cohort of children with NAFLD. Methods: Two hundred and eighty-eight consecutive Caucasian Italian overweight/obese children with biopsy-proven NAFLD were included in the study. We examined the relative association of each histological feature of NAFLD with metabolic alterations, insulin-resistance, I148M polymorphism in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene, and birthweight relative to gestational age. Results: In the whole NAFLD cohort, 12.2% of patients were SGA, 62.8% appropriate for gestational age (AGA), and 25% large for gestational age (LGA). SGA children had a higher prevalence of severe steatosis (69%) and severe portal inflammation (14%) compared with the AGA and LGA groups. Notably, severe steatosis (>66%) was decreasing from SGA to AGA and LGA, whereas the prevalence of moderate steatosis (33–66%) was similar in three groups. The prevalence of type 1 NAFLD is higher in the LGA group with respect to the other two groups (25% vs.5.2% vs.9.4%), whereas the SGA group shows a higher prevalence of overlap type (85.8%) with respect to the LGA group (51.4%) but not compared with the AGA group (75%). At multivariable regression analysis, SGA at birth increased fourfold the likelihood of severe steatosis (odds ratio (OR) 4.0, 95% confidence interval (CI) 1.43–10.9,P=0.008) and threefold the likelihood of NAFLD Activity Score (NAS)≥5 (OR 2.98, 95% CI 1.06–8.33,P=0.037) independently of homeostasis model assessment of insulin resistance and PNPLA3 genotype. The PNPLA3-CC wild-type genotype was the strongest independent predictor of the absence of significant fibrosis (OR 0.26, 95% CI 0.13–0.52,P=<0.001). Conclusions: In children with NAFLD, the risk of severe steatosis is increased by SGA at birth, independent of and in addition to other powerful risk factors (insulin-resistance and I148M variant of thePNPLA3gene). © The American College of Gastroenterology 2017. All Rights Reserved.