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

## TL;DR

Researchers identified three distinct metabolic subtypes of pediatric liver disease using clinical and metabolomics data, which could help guide more targeted treatments.

## Contribution

The study introduces a novel approach to classify pediatric MASLD into distinct metabotypes using unsupervised clustering and metabolomics.

## Key findings

- Three metabotypes were identified: early-mild, cardiometabolic, and inflammatory-fibrotic, each with distinct clinical and metabolic features.
- The inflammatory-fibrotic group showed altered tryptophan metabolism and elevated kynurenine pathway metabolites linked to fibrosis.
- Branched-chain amino acid degradation and purine metabolism were enriched in the cardiometabolic group.

## 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.

Here the authors combine clinical and metabolomics data to identify distinct metabotypes of pediatric metabolic dysfunction-associated steatotic liver disease (MASLD). The results provide information regarding heterogeneity of MASLD presentation, but require validation in independent cohorts.