Author information

¹Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Saint Louis University, St. Louis, Missouri, USA.

²HHEAR Data Center, Icahn School of Medicine at Mount Sinai, Statistical Services and Methods Development Resource, New York, New York, USA.

³Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

⁴Department of Pediatrics, Division of Gastroenterology, UC San Diego, La Jolla, California and Department of Gastroenterology, Rady Children's Hospital, San Diego, California, USA.

⁵Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, San Francisco Benioff Children's Hospital, University of California, San Francisco, California, USA.

⁶Pediatrics Institute, Cleveland Clinic and Cleveland Clinic Children's Hospital, Cleveland, Ohio, USA.

⁷Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Indiana University School of Medicine/Riley Hospital for Children, Indianapolis, Indiana, USA.

⁸Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.

⁹Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

¹⁰Department of Pediatrics, Division of Gastroenterology, UC San Diego, La Jolla, California, USA.

¹¹Department of Gastroenterology, Pacific Rim Pathology, San Diego, California, USA.

¹²Department of Pathology, Saint Louis University, St. Louis, Missouri, USA.

¹³Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

¹⁴Division of Gastroenterology and Hepatology, Saint Louis University, St. Louis, Missouri, USA.

¹⁵Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA.

Abstract

Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is common in children. We hypothesized environmental toxins could drive progression to metabolic dysfunction-associated steatohepatitis (MASH), and assayed serum toxins and metabolites in children with histologically characterized MASLD/MASH.

Methods: Environmental chemicals, common in household items, perfluoroalkyl substances (PFAS), brominated flame retardants (PBDEs), and metabolic profiles were assayed in children enrolled in the multicenter NASH Clinical Research Network Pediatric Database 2. Mixture models, using repeated holdout weighted quantile sum regression (WQSrh) were run in addition to single chemical/metabolite logistic regression. For metabolomic analyses, random subset version of WQSrh was used for the large number of predictors versus participants. Nominal and false discovery rate (FDR) p-values (two-sided) were computed.

Results: Four hundred and thirty-five children distributed across MASH (n = 293) and MASLD (n = 142), with 304 (69.9%) males. Mean (standard deviation) for Nonalcoholic Steatohepatitis Score (NAS) and alanine aminotransferase (ALT) for MASLD were 3.1 (1.0), 67.9 (43.4), and for MASH 4.2 (1.4), 144 (121). There was an inverse association between PFAS/PBDE mixture and MASH versus MASLD, lobular inflammation (p = 0.026), NAS (p = 0.009, FDR p = 0.04), and log-transformed ALT (p = 0.005, FDR p = 0.025) driven by perfluorohexane sulfonate (PFHxS). Metabolites from positive hydrophilic interaction liquid chromatography mode, biliverdin (p = 0.002) and 1-methylhistidine (associated with meat ingestion, p = 0.02) and reverse phase negative mode, hippuric acid (solvent exposure, p = 0.022) significantly associated with MASH.

Conclusions: Significant negative PFAS/PBDE mixture effect and odds of MASH were dominated by PHFXS. Several metabolites are significantly associated with MASH which inform mechanistic pathways and could drive key therapeutic and diagnostic strategies in children.