Interplay of childhood metabolic dysfunction-associated steatotic liver disease and obesity in the development of youth-onset type 2 diabetes

Table 1 Summary of quality assessment outcomes for included studies

Study type	Assessment tool	Number of studies	Quality scores/ratings	Key observations
Systematic reviews	PRISMA 2020	15	Mean score: 22/27 (range: 20-25)	Most adhered to PRISMA. Minor issues included unreported funding or protocols
Observational studies	Newcastle-Ottawa Scale	30	Mean score: 7.2/9 (range: 6-8)	Limitations included incomplete confounder adjustment and follow-up losses
Randomized controlled trials	Cochrane risk of bias 2	25	Low risk: 15, some concerns: 8, high risk: 2	High-risk studies had issues with randomization or missing data. Most had adequate blinding

PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Table 2 Key biomarkers and imaging techniques for pediatric metabolic dysfunction-associated steatotic liver disease

Biomarker/technique	Type	Utility in MASLD	Ref.
ALT	Serum enzyme	Indicates liver injury; used for screening but not specific to MASLD	Vos et al[72], Chan et al[73]
Aspartate aminotransferase	Serum enzyme	Complements ALT in screening for liver damage; like ALT, has low sensitivity	Vos et al[72], Chan et al[73]
Adiponectin	Serum hormone	Lower levels are associated with increased liver fat and inflammation; potential marker for metabolic dysfunction	De Silva et al[82], Mierzwa et al[83]
High-sensitivity C-reactive protein	Serum protein	Indicates systemic inflammation; elevated in obese children with MASLD	Fahed et al[44], Kim et al[84]
Cytokeratin-18	Serum marker	Marker of liver cell death; elevated in steatohepatitis, indicating disease severity	Chen et al[85], Garg et al[86], Jayasekera et al[87]
Ultrasound	Imaging	Detects liver fat but cannot determine disease severity; has low sensitivity	Jia et al[81], Hajibonabi et al[88]
FibroScan	Imaging	Measures liver stiffness to assess fibrosis; non-invasive alternative to biopsy	Kwon et al[80], Jayasekera et al[87]
Magnetic resonance imaging-proton density fat fraction	Imaging	Accurately measures liver fat content; useful for monitoring disease progression	Jia et al[81], Jayasekera et al[87]

ALT: Alanine aminotransferase; MASLD: Metabolic dysfunction-associated steatotic liver disease.

Table 3 Summary of studies on pediatric metabolic dysfunction-associated steatotic liver disease, obesity, and youth-onset type 2 diabetes

Parameter	Study design	Sample size	Study population	Mean age (years)	MASLD diagnostic criteria	Main outcomes	Clinical implication	Ref.
Prevalence and risk factors of pediatric MASLD	Systematic review and meta-analysis	22 studies	Children and adolescents globally	3-19	Ultrasound, biopsy	MASLD prevalence 76% in general pediatric population, 34% in obese children	Highlights need for routine screening in obese youth	Anderson et al[15], 2015
Clinical guidelines for pediatric MASLD	Expert consensus guideline	N/A	Pediatric MASLD cases	5-18	Biopsy, imaging	Guideline recommends screening and lifestyle therapy	Supports early identification and structured management	Vos et al[72], 2017
Lifestyle intervention in pediatric obesity and MASLD	RCT	107 participants	United Kingdom children with obesity and MASLD	12-16	Ultrasound	Combined diet and exercise reduced liver fat by 8%	Lifestyle interventions effective for pediatric MASLD management	Newton et al[14], 2017
Genetic factors in pediatric MASLD	Cohort study	475 participants	European obese children	10-18	Ultrasound, biopsy	Patatin-like phospholipase domain-containing protein 3 variant increased MASLD risk 2-fold	Genetic screening may help target high-risk children	Mann et al[89], 2018
Effect of low-sugar diet on liver fat	RCT	40 participants	Obese adolescent boys (United States)	14	Ultrasound, MRI-PDFF	Reduced hepatic fat with low-sugar diet	Supports sugar reduction as therapy	Schwimmer et al[15], 2019
Usefulness of FibroScan in pediatric MASLD	Observational study	67 participants	Korean children with suspected MASH	12.5	FibroScan, ultrasound	FibroScan accurately assessed liver stiffness (P ≤ 0.009)	Supports use of non-invasive tools	Kwon et al[80], 2019
Liraglutide in adolescent obesity	RCT	251 participants	Adolescents with obesity	14.7	Ultrasound	Reduced BMI (P < 0.01); ≥ 5% and ≥ 10% BMI reductions were higher (P < 0.01) and improved metabolic markers	Glucagon-like peptide-1 agonists show promise; more studies needed	Kelly et al[16], 2020
Effect of vitamin E on pediatric MASH	RCT	50 participants	Obese, non-diabetic children aged 10-14 with MASLD (Iran)	12	Ultrasound, biopsy	Significant improvement in liver steatosis, ALT, and insulin levels (P = 0.007)	Vitamin E may support lifestyle changes in managing pediatric MASLD	Homaei et al[18], 2022
Liver steatosis as a metabolic risk marker	Review and clinical study	N/A	Italian obese children	10-18	Ultrasound, MRI-MASLD	Strong association with insulin resistance and T2D	Steatosis screening may identify at-risk children	Neri et al[90], 2022
MRI-PDFF FibroScan diagnostic accuracy	Meta-analysis	8 studies	Suspected pediatric MASLD cases	8-18	MRI-PDFF, FibroScan	MRI-PDFF showed higher sensitivity	MRI-PDFF may be superior for early diagnosis	Jia et al[81], 2022
Semaglutide in pediatric obesity	RCT	201 participants	Adolescents with obesity and at least one weight-related comorbidity, across multiple countries	15.0	Ultrasound, MRI-PDFF	BMI decreased (P < 0.001); improvements in waist circumference, HbA1c, lipids (except high-density lipoprotein), and ALT; higher incidence of gastrointestinal adverse events (62% vs 42%)	Semaglutide significantly reduced BMI and liver fat in adolescents with obesity, showing promise as a treatment for MASLD	Weghuber et al[17], 2022
Mental health comorbidities in youth-onset T2D	Retrospective cohort study	1236 participants	Canadian youth with T2D	14-18	N/A	30.2% had comorbidities; linked to poor HbA1c and adherence	Mental health screening is essential to improve care	Sellers et al[91], 2022
Birth weight and prediabetes	Cross-sectional analysis	1396 participants	United States adolescents aged 12-15 years	13.5	N/A	Low/high birth weight increased prediabetes risk (odds ratio = 1.93; 95%CI: 1.10-3.38; P < 0.05)	Birth weight may predict prediabetes risk early	Sanjeevi et al[92], 2022
Global burden of MASLD and T2D	Systematic review	53 studies	Global pediatric population	3-19	Ultrasound, MRI-PDFF, biopsy	MASLD increased T2D risk by 2.3-fold	Supports integrated screening for MASLD and T2D	Eslam et al[93], 2020
Psychosocial barriers in MASLD and obesity	Narrative review	N/A	Global pediatric population	3-18	Ultrasound, biopsy	Stress and stigma hinder lifestyle adherence in youth with MASLD and obesity	Behavioral strategies needed to address stigma	Piester et al[4], 2023
Global prevalence of pediatric MASLD	Systematic review and meta-analysis	74 studies	Global children and adolescents	3-19	Ultrasound, MRI-PDFF, biopsy	Overall prevalence 13%; 47% in obese children	Routine screening recommended in obese youth	Lee et al[1], 2024
Natural history and progression of MASLD in adolescents	Narrative review	3500 (subset of adolescents)	Adolescents with obesity or T2D (global cohort)	16.5 ± 2.1	Ultrasound, elevated ALT (> 40 U/L), and metabolic risk factors (e.g., obesity, insulin resistance)	MASLD prevalence in adolescents was 40%-45% in obese populations; 5%-7% progressed to MASH within 5 years; insulin resistance and obesity were key drivers of fibrosis progression	Highlights the need for early screening and lifestyle interventions in adolescents to prevent MASLD progression to MASH and fibrosis	Hagström et al[94], 2024
MASLD and T2D risk in obese youth	Cohort study	12300 participants	Obese Swedish youth	15.2	Ultrasound, biopsy	MASLD increased T2D risk 2.7-fold by age 30	Early MASLD screening advised for obese youth	Putri et al[3], 2024
Tocotrienol-rich vitamin E vs metformin in MASLD	RCT	80 participants	Obese adolescents with biopsy-proven MASLD	14-18	Biopsy	Vitamin E reduced liver fat more effectively than metformin	Vitamin E is a promising therapy for pediatric MASLD	Al-Baiaty et al[19], 2024
Oxidative stress in obesity and MASLD	Review and mechanistic study	N/A	Obese children with metabolic syndrome	10-18	Ultrasound, biopsy	Oxidative stress mediates MASLD and dyslipidemia	Targeting oxidative stress may slow MASLD progression	Accacha et al[48], 2025

ALT: Alanine aminotransferase; BMI: Body mass index; HbA1c: Hemoglobin A1c; MASH: Metabolic dysfunction-associated steatohepatitis; MASLD: Metabolic dysfunction-associated steatotic liver disease; MRI: Magnetic resonance imaging; MRI-PDFF: Magnetic resonance imaging-proton density fat fraction; N/A: Not applicable; RCT: Randomized controlled trial; T2D: Type 2 diabetes.