Perfluoroalkyl substances and severity of nonalcoholic fatty liver in Children: An untargeted metabolomics approach.
Journal
Environment international
ISSN: 1873-6750
Titre abrégé: Environ Int
Pays: Netherlands
ID NLM: 7807270
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
30
05
2019
revised:
23
09
2019
accepted:
23
09
2019
pubmed:
21
11
2019
medline:
5
9
2020
entrez:
21
11
2019
Statut:
ppublish
Résumé
Toxicant-associated steatohepatitis has been described in adults but less is known regarding the role of toxicants in liver disease of children. Perfluoroalkyl substances (PFAS) cause hepatic steatosis in rodents, but few previous studies have examined PFAS effects on severity of liver injury in children. We aimed to examine the relationship of PFAS to histologic severity of nonalcoholic fatty liver disease (NAFLD) in children. Seventy-four children with physician-diagnosed NAFLD were recruited from Children's Healthcare of Atlanta between 2007 and 2015. Biopsy-based liver histological features were scored for steatosis, lobular and portal inflammation, ballooning, and fibrosis. Plasma concentrations of perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonic acid (PFHxS), and untargeted plasma metabolomic profiling, were determined using liquid chromatography with high-resolution mass spectrometry. A metabolome-wide association study coupled with pathway enrichment analysis was performed to evaluate metabolic dysregulation associated with PFAS. A structural integrated analysis was applied to identify latent clusters of children with more severe form of NAFLD based on their PFAS levels and metabolite pattern. Patients were 7-19 years old, mostly boys (71%), Hispanic (51%), and obese (85%). The odds of having nonalcoholic steatohepatitis (NASH), compared to children with steatosis alone, was significantly increased with each interquartile range (IQR) increase of PFOS (OR: 3.32, 95% CI: 1.40-7.87) and PFHxS (OR: 4.18, 95% CI: 1.64-10.7). Each IQR increase of PFHxS was associated with increased odds for liver fibrosis (OR: 4.44, 95% CI: 1.34-14.8), lobular inflammation (OR: 2.87, 95% CI: 1.12-7.31), and higher NAFLD activity score (β coefficient 0.46; 95% CI: 0.03, 0.89). A novel integrative analysis identified a cluster of children with NASH, characterized by increased PFAS levels and altered metabolite patterns including higher plasma levels of phosphoethanolamine, tyrosine, phenylalanine, aspartate and creatine, and decreased plasma levels of betaine. Ηigher PFAS exposure was associated with more severe disease in children with NAFLD. PFAS may be an important toxicant contributing to NAFLD progression; however larger, longitudinal studies are warranted to confirm these findings.
Sections du résumé
BACKGROUND
Toxicant-associated steatohepatitis has been described in adults but less is known regarding the role of toxicants in liver disease of children. Perfluoroalkyl substances (PFAS) cause hepatic steatosis in rodents, but few previous studies have examined PFAS effects on severity of liver injury in children.
OBJECTIVES
We aimed to examine the relationship of PFAS to histologic severity of nonalcoholic fatty liver disease (NAFLD) in children.
METHODS
Seventy-four children with physician-diagnosed NAFLD were recruited from Children's Healthcare of Atlanta between 2007 and 2015. Biopsy-based liver histological features were scored for steatosis, lobular and portal inflammation, ballooning, and fibrosis. Plasma concentrations of perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonic acid (PFHxS), and untargeted plasma metabolomic profiling, were determined using liquid chromatography with high-resolution mass spectrometry. A metabolome-wide association study coupled with pathway enrichment analysis was performed to evaluate metabolic dysregulation associated with PFAS. A structural integrated analysis was applied to identify latent clusters of children with more severe form of NAFLD based on their PFAS levels and metabolite pattern.
RESULTS
Patients were 7-19 years old, mostly boys (71%), Hispanic (51%), and obese (85%). The odds of having nonalcoholic steatohepatitis (NASH), compared to children with steatosis alone, was significantly increased with each interquartile range (IQR) increase of PFOS (OR: 3.32, 95% CI: 1.40-7.87) and PFHxS (OR: 4.18, 95% CI: 1.64-10.7). Each IQR increase of PFHxS was associated with increased odds for liver fibrosis (OR: 4.44, 95% CI: 1.34-14.8), lobular inflammation (OR: 2.87, 95% CI: 1.12-7.31), and higher NAFLD activity score (β coefficient 0.46; 95% CI: 0.03, 0.89). A novel integrative analysis identified a cluster of children with NASH, characterized by increased PFAS levels and altered metabolite patterns including higher plasma levels of phosphoethanolamine, tyrosine, phenylalanine, aspartate and creatine, and decreased plasma levels of betaine.
CONCLUSIONS
Ηigher PFAS exposure was associated with more severe disease in children with NAFLD. PFAS may be an important toxicant contributing to NAFLD progression; however larger, longitudinal studies are warranted to confirm these findings.
Identifiants
pubmed: 31744629
pii: S0160-4120(19)31819-7
doi: 10.1016/j.envint.2019.105220
pmc: PMC6944061
mid: NIHMS1063439
pii:
doi:
Substances chimiques
Fluorocarbons
0
Sulfonic Acids
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
105220Subventions
Organisme : NIEHS NIH HHS
ID : R21 ES029681
Pays : United States
Organisme : NIEHS NIH HHS
ID : T32 ES012870
Pays : United States
Organisme : NIEHS NIH HHS
ID : P01 ES022845
Pays : United States
Organisme : NIEHS NIH HHS
ID : R21 ES028903
Pays : United States
Organisme : NIEHS NIH HHS
ID : U2C ES026560
Pays : United States
Organisme : NIEHS NIH HHS
ID : F32 ES029828
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH107205
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES019776
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA196569
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES029944
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES007048
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA140561
Pays : United States
Organisme : NIH HHS
ID : S10 OD018006
Pays : United States
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.
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