Environmental toxicants modulate disease severity in pediatric metabolic dysfunction-associated steatohepatitis

Ajay K Jain¹, Stefanie A Busgang², Chris Gennings², Katherine P Yates³, Jeffrey B Schwimmer^{4

5}, Philip Rosenthal⁶, Karen F Murray⁷, Jean P Molleston⁸, Ann Scheimann⁹, Stavra A Xanthakos¹⁰, Cynthia A Behling^{4

11}, Danielle Carpenter¹², Mark Fishbein¹³, Brent A Neuschwander-Tetri¹⁴, James Tonasia³, Miriam B Vos¹⁵

Affiliations

¹ Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Saint Louis University, St. Louis, Missouri, USA.
² HHEAR Data Center, Icahn School of Medicine at Mount Sinai, Statistical Services and Methods Development Resource, New York, New York, USA.
³ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
⁴ Department of Pediatrics, Division of Gastroenterology, UC San Diego, La Jolla, California, USA.
⁵ Department of Gastroenterology, Rady Children's Hospital, San Diego, California, USA.
⁶ Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, San Francisco Benioff Children's Hospital, University of California, San Francisco, California, USA.
⁷ Pediatrics Institute, Cleveland Clinic and Cleveland Clinic Children's Hospital, Cleveland, Ohio, USA.
⁸ Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Indiana University School of Medicine/Riley Hospital for Children, Indianapolis, Indiana, USA.
⁹ Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
¹⁰ Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
¹¹ Department of Gastroenterology, Pacific Rim Pathology, San Diego, California, USA.
¹² Department of Pathology, Saint Louis University, St. Louis, Missouri, USA.
¹³ Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
¹⁴ Division of Gastroenterology and Hepatology, Saint Louis University, St. Louis, Missouri, USA.
¹⁵ Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA.

PMID: 39282813
PMCID: PMC11955998 (available on 2025-11-01)
DOI: 10.1002/jpn3.12346

Multicenter Study

Environmental toxicants modulate disease severity in pediatric metabolic dysfunction-associated steatohepatitis

Ajay K Jain et al. J Pediatr Gastroenterol Nutr. 2024 Nov.

. 2024 Nov;79(5):943-953.

doi: 10.1002/jpn3.12346. Epub 2024 Sep 16.

Authors

Affiliations

¹ Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Saint Louis University, St. Louis, Missouri, USA.
² HHEAR Data Center, Icahn School of Medicine at Mount Sinai, Statistical Services and Methods Development Resource, New York, New York, USA.
³ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
⁴ Department of Pediatrics, Division of Gastroenterology, UC San Diego, La Jolla, California, USA.
⁵ Department of Gastroenterology, Rady Children's Hospital, San Diego, California, USA.
⁶ Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, San Francisco Benioff Children's Hospital, University of California, San Francisco, California, USA.
⁷ Pediatrics Institute, Cleveland Clinic and Cleveland Clinic Children's Hospital, Cleveland, Ohio, USA.
⁸ Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Indiana University School of Medicine/Riley Hospital for Children, Indianapolis, Indiana, USA.
⁹ Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
¹⁰ Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
¹¹ Department of Gastroenterology, Pacific Rim Pathology, San Diego, California, USA.
¹² Department of Pathology, Saint Louis University, St. Louis, Missouri, USA.
¹³ Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
¹⁴ Division of Gastroenterology and Hepatology, Saint Louis University, St. Louis, Missouri, USA.
¹⁵ Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA.

PMID: 39282813
PMCID: PMC11955998 (available on 2025-11-01)
DOI: 10.1002/jpn3.12346

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), polybrominated flame retardants (polybrominated diphenyl ethers [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 (WQS_rh) were run in addition to single chemical/metabolite logistic regression. For metabolomic analyses, random subset version of WQS_rh 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.

Keywords: MASH; MASLD; PHFXS; children; metabolites.

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Conflict of interest statement

CONFLICT OF INTEREST STATEMENT

Ajay Jain is a consultant for Mirum and Camp 4. Philip Rosenthal has research support from Abbvie, Albireo, Arrowhead, Gilead, Merck, Mirum, Takeda, and Travere. Philip Rosenthal is a consultant for Albireo, Audentes, BioMarin, Dicerna, Encoded, Gilead, MedinCell, Mirum, RNAV8, Takeda, Taysha, Travere. Jean Molleston reports Abbie, Albireo, Gillead, Shire, and CF Foundation. Karen Murray reports Albireo, Gilead, ICN Board of Directors, Brent Tetri reports Akero, Arrowhead, Boehringer Ingelheim, BMS, Clinical Care Options, Durect, GSK, Glympse, Hepion, High Tide, HistoIndex, Labcorp, LG Chem, Madrigal, Merck, Sagimet, Senseion, Target RWE, 89Bio; Stock options: HepGene, HeptaBio; Institutional research grants: BMS, HighTide, Intercept, Inventiva, Madrigal. Stavra Xanthakos reports Target MASH. The remaining authors declare no conflict of interest.

References

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Environmental toxicants modulate disease severity in pediatric metabolic dysfunction-associated steatohepatitis

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Environmental toxicants modulate disease severity in pediatric metabolic dysfunction-associated steatohepatitis

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