Clinically distinct metabotypes of pediatric MASLD identified through unsupervised clustering of NASH CRN data

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease worldwide, yet treatment remains "one size fits all," despite phenotypic heterogeneity. We analyzed clinical and metabolomics data from 514 children (ages 5-18, 73% male) with biopsy-proven MASLD across three NASH Clinical Research Network studies. Unsupervised clustering of clinical data identified three distinct metabotypes: early-mild (49.4%, youngest, lowest lipids, liver enzymes, insulin resistance), cardiometabolic (36.8%, highest waist circumference, lipids, uric acid, SBP), and inflammatory-fibrotic (13.8%, highest liver enzymes, steatohepatitis, advanced fibrosis). Integrative network and pathway enrichment analyses revealed alterations in tryptophan metabolism within the inflammatory-fibrotic group, including elevated kynurenine pathway metabolites, which were significantly correlated with fibrosis stage. Branched-chain amino acid degradation, butanoate, and purine metabolism demonstrated greater enrichment in the cardiometabolic group. Here, we show that pediatric MASLD subtypes differ in clinical and metabolic features, providing a framework for targeted interventions, with validation needed in independent cohorts.

Authors

Institutions

Publication Details

Journal
Nature Communications
Published
2026-02-24
DOI
https://doi.org/10.1038/s41467-026-69735-z
Primary Topic
Liver Disease Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Clinically distinct metabotypes of pediatric MASLD identified through unsupervised clustering of NASH CRN data

Rishikesan Kamaleswaran, Georgia M. Davis, Zachery Jarrell, Helaina Huneault et al.
Nature Communications
Liver Disease Diagnosis and Treatment
article

Clinically distinct metabotypes of pediatric MASLD identified through unsupervised clustering of NASH CRN data

Rishikesan Kamaleswaran, Georgia M. Davis, Zachery Jarrell, Helaina Huneault, Mark Fishbein, Jean A. Welsh, Matthew Ryan Smith, Terryl J. Hartman, Ana Ramirez Tovar, Pradeep Tiwari, S. Bai, B A Neuschwander-Tetri, Cristian Sanchez-Torres, Dean P. Jones, Ajay K. Jain, Scott Gillespie, Katherine P. Yates, Jeffrey B. Schwimmer, Jean P. Molleston, Miriam B. Vos
article en

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease worldwide, yet treatment remains "one size fits all," despite phenotypic heterogeneity. We analyzed clinical and metabolomics data from 514 children (ages 5-18, 73% male) with biopsy-proven MASLD across three NASH Clinical Research Network studies. Unsupervised clustering of clinical data identified three distinct metabotypes: early-mild (49.4%, youngest, lowest lipids, liver enzymes, insulin resistance), cardiometabolic (36.8%, highest waist circumference, lipids, uric acid, SBP), and inflammatory-fibrotic (13.8%, highest liver enzymes, steatohepatitis, advanced fibrosis). Integrative network and pathway enrichment analyses revealed alterations in tryptophan metabolism within the inflammatory-fibrotic group, including elevated kynurenine pathway metabolites, which were significantly correlated with fibrosis stage. Branched-chain amino acid degradation, butanoate, and purine metabolism demonstrated greater enrichment in the cardiometabolic group. Here, we show that pediatric MASLD subtypes differ in clinical and metabolic features, providing a framework for targeted interventions, with validation needed in independent cohorts.

Nature Communications
Northwestern University (US), Grand Rapids Community College (US), Cincinnati Children's Hospital Medical Center (US), Sharp Memorial Hospital (US), Johns Hopkins University (US), Emory University (US), Duke University (US), Riley Hospital for Children (US), University of California San Diego (US), Rady Children's Hospital-San Diego (US), Helen DeVos Children's Hospital (US), Children's Healthcare of Atlanta (US), Atlanta VA Health Care System (US), Saint Louis University (US), Indiana University – Purdue University Indianapolis (US), University of Cincinnati (US), Michigan State University (US)
Good health and well-being
Openalex Percentile: Top 45%
Liver Disease Diagnosis and Treatment
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.