Alanine Aminotransferase and Gamma-Glutamyl Transpeptidase Predict Histologic Improvement in Pediatric Nonalcoholic Steatohepatitis

• Type of Material: Article
• Authors: Kimberly P Newton, University of California San Diego; Joel E Lavine, Columbia University; Laura Wilson, Johns Hopkins University; Cynthia Behling, University of California San Diego; Miriam Vos, Emory University; Jean P Molleston, Riley Children’s Hospital; Philip Rosenthal, University of California San Francisco; Tamir Miloh, Texas Childrens Hosp; Mark H Fishbein, Ann & Robert H. Lurie Children’s Hospital of Chicago; Ajay K Jain, Saint Louis University; Karen F Murray, Cleveland Clinic Children’s Hospital
• Language: English
• Date: 2020-11-30
• Publisher: WILEY
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 by the American Association for the Study of Liver Diseases.
• Final Published Version (URL): http://dx.doi.org/10.1002/hep.31317
• Title of Journal or Parent Work: HEPATOLOGY
• Volume: 73
• Issue: 3
• Start Page: 937
• End Page: 951
• Grant/Funding Information: The Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (grants U01DK061718, U01DK061728, U01DK061731, U01DK061732, U01DK061734, U01DK061737, U01DK061738, U01DK061730, U01DK061713). Additional support is received from the National Center for Advancing Translational Sciences (NCATS) (grants UL1TR000077, UL1TR000150, UL1TR000424, UL1TR000006, UL1TR000448, UL1TR000040, UL1TR000100, UL1TR000004, UL1TR000423, UL1TR000454). The CyNCh trial was conducted by the NASH CRN and supported in part by the Intramural Research Program of the National Cancer Institute and by a Collaborative Research and Development Agreement (CRADA) between NIDDK and Raptor Pharmaceuticals.
• Keywords: Life Sciences & Biomedicine; GLUTATHIONE; DIAGNOSIS; Gastroenterology & Hepatology; FATTY LIVER-DISEASE; OBESE CHILDREN; Science & Technology; ADULTS; OXIDATIVE STRESS; GASTROENTEROLOGY

Abstract

Background and Aims: Predictive, noninvasive tools are needed to monitor key features of nonalcoholic fatty liver disease (NAFLD) in children that relate to improvement in liver histology. The purpose of this study was to evaluate the relationship between liver chemistries and liver histology using data from the CyNCh (Cysteamine Bitartrate Delayed-Release for the Treatment of NAFLD in Children) clinical trial. Approach and Results: This study included 146 children. Improvement in liver histology, defined as decrease in nonalcoholic fatty liver disease (NAFLD) Activity Score ≥2 points without worsening of fibrosis, occurred in 43 participants (30%). There were 46 participants with borderline zone 1 nonalcoholic steatohepatitis (NASH) at baseline, with resolution in 28% (12 of 46). Multivariate models were constructed using baseline and change in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) at 52 weeks, for improvement in (1) liver histology primary outcome, (2) borderline zone 1 NASH, and (3) fibrosis. For improvement in histology, the model (P < 0.0001) retained baseline and change in GGT (area under the receiver operating characteristic [AUROC], 0.79; 95% confidence interval [CI], 0.71-0.87). For borderline zone 1 NASH, the model (P = 0.0004) retained baseline and change in ALT (AUROC, 0.80; 95% CI, 0.67-0.93). For fibrosis, the model (P < 0.001) retained baseline and change in ALT (AUROC, 0.80; 95% CI, 0.67-0.93). Additional clinical parameters were added to the models using Akaike’s information criterion selection, and significantly boosted performance: improvement in histology with AUROC of 0.89 (95% CI, 0.82-0.95), borderline zone 1 NASH with AUROC of 0.91 (95% CI, 0.83-0.99), and fibrosis with AUROC of 0.89 (95% CI, 0.82-0.94). Models were validated using data from the TONIC (Treatment of Nonalcoholic Fatty Liver Disease in Children) trial. Conclusions: In children with NAFLD, dynamic changes in serum ALT and GGT are associated with change in liver histology and appear to be powerful indicators of histological response.