Precision nutrition for pediatric metabolic dysfunction-associated steatotic liver disease (MASLD): Addressing the heterogeneity of MASLD in children Restricted; Files Only

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is the most common chronic liver disease in children. Emerging research in adults highlights MASLD as a heterogeneous condition influenced by various biological and environmental factors. Precision nutrition approaches have shown promise in improving health outcomes by tailoring interventions to these individual differences. However, the phenotypic heterogeneity of pediatric MASLD remains poorly understood, presenting a significant barrier to developing personalized interventions. 

Therefore, the purpose of this dissertation was to gain insight into the heterogeneity of pediatric MASLD and the potential role of precision nutrition in prevention and treatment. First, unsupervised clustering based on clinical and metabolomics data identified three distinct metabolic phenotypes (metabotypes), each with unique metabolic profiles, highlighting the need for targeted interventions.

To further explore metabolic differences, glycemic variability was assessed in prepubertal Hispanic children at risk for MASLD using continuous glucose monitoring data. Mild hepatic steatosis (≥3%) was strongly associated with glycemic derangement, suggesting a need for earlier screening and intervention than previously recognized.

Lastly, differences between responders (≥5% hepatic steatosis reduction) and non-responders (<5%) to a low-free sugar diet intervention were analyzed. Responders exhibited lower baseline levels of ceramides and diacylglycerols, along with greater reductions in palmitate-enriched triglycerides. In contrast, non-responders had more lipotoxic lipid profiles at baseline, suggesting greater disease severity and a potential need for longer or more intensive interventions.

These findings provide novel insights into the heterogeneity of pediatric MASLD, emphasizing the need for tailored therapeutic strategies. Identifying metabotypes, understanding glycemic variability, and characterizing omics-based differences in dietary response highlight precision nutrition as a promising approach for optimizing MASLD prevention and treatment. Further research is needed to validate these findings and assess long-term outcomes to guide the development of more targeted strategies for pediatric MASLD.

Table of Contents

Chapter 1: Introduction .................................................................................................................................1 

Chapter 2: Background .................................................................................................................................3 

  2.1. Significance of the problem................................................................................................................3 

  2.2. Heterogeneity in the pathogenesis of MASLD………………………………..…………....…….....4 

  2.3. Current subtypes of MASLD……………........................................................................................10 

  2.4. Precision nutrition approaches for MASLD ……………………………………............................14 

  2.5. Summary, specific aims, and hypotheses..........................................................................................17 

Chapter 3: Expanded Methods.....................................................................................................................20 

3.1. Introduction: ....................................................................................................................................20 

3.2. Overview of Parent Studies: ............................................................................................................20 

3.3. Clinical, Anthropometric, and Histological Assessment Methods: ................................................22 

3.4. Continuous Glucose Monitoring Methods: .....................................................................................24 

3.5. High-Resolution Metabolomics & Lipidomics Methods: ...............................................................26 

3.6. Statistical and Bioinformatics Analyses: ........................................................................................31 

Chapter 4: Clinically Distinct Metabotypes of Pediatric Metabolic Dysfunction-Associated Steatotic Liver Disease:

An Unsupervised Machine Learning Analysis of Children Enrolled in NASH CRN Studies .............................37 

4.1. Abstract: ..........................................................................................................................................38

4.2. Introduction: ....................................................................................................................................39

4.3. Methods: ..........................................................................................................................................40

4.4. Results: ............................................................................................................................................47

4.5. Discussion: ......................................................................................................................................51

Chapter 5: Hepatic Steatosis is Associated with Glycemic Dysregulation in Prepubertal Hispanic Children.….66

5.1. Abstract: ..........................................................................................................................................67 

5.2. Introduction: ....................................................................................................................................68 

5.3. Methods: ..........................................................................................................................................69 

5.4. Results: ............................................................................................................................................74 

5.5. Discussion: ......................................................................................................................................76 

Chapter 6: Lipidome Changes Associated with a Diet-Induced Reduction in Hepatic Fat among Adolescent Boys with

Metabolic Dysfunction-Associated Steatotic Liver Disease .........................................................................89 

6.1. Abstract: ..........................................................................................................................................90 

6.2. Introduction: ....................................................................................................................................90 

6.3. Materials And Methods: ................................................................................................................. 93 

6.4. Results: ..........................................................................................................................................100 

6.5. Discussion: ....................................................................................................................................106 

Chapter 7: Discussion………………........................................................................................................120 

7.1. Precision Nutrition and Metabolic Heterogeneity in Pediatric MASLD:......................................120 

7.2. Clinical and public health implications: ........................................................................................121

7.3. Strengths & Limitations: ...............................................................................................................123   

7.4. Future directions for research and clinical care: ...........................................................................123 

Chapter 8: Conclusions .............................................................................................................................125 

References .................................................................................................................................................126 

About this Dissertation

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School	Laney Graduate School
Department	Nutrition and Health Sciences
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Health Sciences, Nutrition
Palavra-chave	metabolism hepatic steatosis youth phenotype nutrition metabolomics
Committee Chair / Thesis Advisor	Miriam B. Vos, Emory University
Committee Members	Jean A. Welsh, Emory University Rishikesan Kamaleswaran, Duke University Terryl J. Hartman, Emory University Dean P. Jones, Emory University Francisco J. Pasquel, Emory University

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