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

Abstract

BACKGROUND

The global increase in childhood and adolescent obesity has significantly contributed to the rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) – a condition now recognized as a key metabolic complication in youth. MASLD significantly increases the risk of youth-onset type 2 diabetes (T2D), particularly among obese individuals. Its asymptomatic progression presents considerable challenges for timely diagnosis and intervention.

AIM

To review epidemiology, pathophysiological mechanisms, and management strategies related to pediatric MASLD, exploring its interaction with obesity and youth-onset T2D.

METHODS

A comprehensive literature search was conducted using PubMed, Scopus, and Google Scholar to identify peer-reviewed studies published between 2015 and 2025. Keywords included “pediatric MASLD”, “childhood obesity”, “youth-onset type 2 diabetes”, “hepatic insulin resistance”, and “noninvasive biomarkers”. Articles were selected based on relevance, methodological quality, and focus on human pediatric populations.

RESULTS

MASLD affects approximately 13% of children globally and up to 47% of those with obesity, with the highest prevalence reported in urban areas of the United States, China, and India. In children and adolescents, excess adiposity is the leading contributor to hepatic steatosis and metabolic dysfunction, particularly when body mass exceeds standard growth benchmarks for age and sex. MASLD increases the risk of adolescent T2D by approximately 2.7-fold. Key pathophysiological mechanisms include hepatic insulin resistance, mitochondrial dysfunction, and chronic inflammation, driven by lipotoxic metabolites such as ceramides and pro-inflammatory cytokines. Lifestyle modifications – particularly low free-sugar diets and structured physical activity – have demonstrated moderate efficacy in reducing hepatic fat and improving metabolic outcomes. Pharmacologic interventions, including glucagon-like peptide-1 receptor agonists such as liraglutide and semaglutide, show potential for weight reduction and glycemic control, though their effects on hepatic histology remain under investigation.

CONCLUSION

MASLD represents a critical metabolic threat in pediatric populations, strongly influenced by obesity and closely associated with increased risk of youth-onset T2D. Effective management requires early detection, multidisciplinary interventions, and equitable access to care. Future research should prioritize the validation of noninvasive diagnostic tools, development of targeted therapies, and reduction of socioeconomic and ethnic disparities in disease burden and treatment outcomes.

Key Words: Pediatric; Metabolic dysfunction-associated steatotic liver disease; Childhood obesity; Type 2 diabetes mellitus; Metabolic syndrome; Non-alcoholic fatty liver disease; Insulin resistance

Core Tip: The global increase in childhood and adolescent obesity has significantly contributed to the rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) – a metabolic complication with significant extrahepatic manifestations in the youth. MASLD represents a critical metabolic threat in pediatric populations, strongly influenced by obesity and is closely associated with increased risk of youth-onset type 2 diabetes (T2D). This comprehensive literature search synthesizes the current evidence on the epidemiological trends, pathophysiological mechanisms, psychological impact, diagnostic challenges, management and prevention strategies related to MASLD in the pediatric population, with particular emphasis on its interplay with obesity and youth-onset T2D.

INTRODUCTION

Metabolic dysfunction-associated steatotic liver disease (MASLD), recently introduced as a more accurate term to replace non-alcoholic fatty liver disease, underscores the central role of metabolic dysfunction in pediatric hepatic steatosis[1]. Recent estimates indicate that MASLD affects nearly 13% of the global pediatric population, with prevalence increasing significantly – up to 47% – among children and adolescents with obesity[2]. Marked geographic variation is observed, especially in rapidly urbanizing countries such as the United States, China, and India, where shifts in lifestyle behaviors have intensified the dual burden of pediatric obesity and MASLD[3].

Among the modifiable contributors, obesity – defined as a body mass index (BMI) at or above the 95^th percentile for age and sex – remains the leading risk factor for MASLD in children, primarily due to its role in promoting hepatic fat accumulation, systemic insulin resistance, and low-grade chronic inflammation[4]. The presence of MASLD significantly heightens the risk of youth-onset type 2 diabetes (T2D), with longitudinal cohort data demonstrating a 2.7-fold increase in T2D incidence among adolescents with MASLD compared to their non-MASLD counterparts[5].

In addition to metabolic and physiological factors, psychosocial determinants – such as chronic stress, social stigma, and emotional distress – further aggravate disease progression by negatively impacting lifestyle behaviors, treatment adherence, and overall clinical outcomes in affected youth[6]. The increasing prevalence of youth-onset T2D is particularly evident in regions undergoing epidemiological transition and is closely linked to the concurrent rise in childhood obesity and MASLD[7].

Despite growing awareness, MASLD remains significantly underdiagnosed in pediatric populations. This is largely attributable to limitations in conventional screening modalities, including liver enzyme assays and ultrasound imaging, which often lack the sensitivity and specificity required for early detection[8]. Furthermore, the absence of standardized diagnostic criteria tailored to children poses a considerable barrier to accurate diagnosis and consistent management[9].

This comprehensive literature search aims to synthesize current evidence on the epidemiological trends, pathophysiological mechanisms, psychological impact, diagnostic challenges, management and prevention strategies related to MASLD in the pediatric population, with particular emphasis on its interplay with obesity and youth-onset T2D.

MATERIALS AND METHODS

Search strategy and data sources

A comprehensive literature search was conducted using PubMed, Scopus, and Google Scholar to identify relevant studies published between January 2015 and May 2025. These databases were chosen for their extensive coverage: (1) PubMed for biomedical literature; (2) Scopus for multidisciplinary research; and (3) Google Scholar for gray literature and recent articles. Other databases, such as Web of Science and EMBASE, were excluded due to significant overlap with Scopus and PubMed and limited resource access, balancing comprehensiveness with feasibility.

The protocol for this systematic review was not registered in PROSPERO; however, a detailed protocol was followed to ensure methodological rigor and transparency.

The search used Medical Subject Headings and free-text keywords, including “pediatric MASLD”, “childhood obesity”, “youth-onset type 2 diabetes”, “hepatic insulin resistance”, “metabolic dysfunction-associated steatotic liver disease”, and “noninvasive biomarkers”. We applied Boolean operators (AND, OR, NOT) to focus on pediatric populations and the interplay of MASLD, obesity, and T2D. Full search queries are provided in Supplementary material.

The search yielded 660 records. After deduplication using EndNote, 420 unique records remained. We screened titles and abstracts, selecting 145 articles for full-text review. Ultimately, 70 studies [30 cohort studies, 25 randomized controlled trials (RCTs), and 15 systematic reviews] met inclusion criteria. We categorized these into epidemiology, pathophysiology, and clinical implications for structured synthesis.

Inclusion and exclusion criteria

Inclusion criteria: (1) Were published between January 2015 and May 2025 in peer-reviewed journals; (2) Focused on individuals under 20 years; (3) Explored associations among obesity, MASLD, and youth-onset T2D; (4) Reported original research or were systematic reviews/meta-analyses; and (5) Were in English and available in full text.

Exclusion criteria: (1) Focused solely on adults or gestational diabetes; (2) Did not investigate MASLD, obesity, and youth-onset T2D relationships; (3) Were case reports, conference abstracts, editorials, or letters; and (4) Were non-English or lacked methodological transparency.

Data extraction

Two reviewers independently screened titles and abstracts, achieving a κ of 0.82 (substantial agreement). Full-text reviews yielded a k of 0.79 for inclusion decisions. We resolved disagreements via discussion or a third reviewer. Extracted data included: (1) Author(s) and year; (2) Study design and population; (3) MASLD and youth-onset T2D diagnostic criteria; and (4) Key metabolic and obesity-related findings.

Quality assessment

The methodological quality of included studies was appraised using standardized evaluation tools: (1) Systematic reviews and meta-analyses [Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)] 2020 for systematic reviews[10]; (2) Newcastle-Ottawa Scale (NOS) for observational studies[11]; and (3) Cochrane risk of bias 2 (RoB 2) for RCTs)[12]. Only moderate- to high-quality studies were included. Inter-reviewer agreement for quality assessments was κ of 0.85 (almost perfect). We resolved disagreements by consensus or a third reviewer. Quality assessment outcomes are summarized in Table 1.

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.

Statistical analysis

We used a narrative synthesis due to significant heterogeneity in study designs, populations, and outcomes, which precluded a meta-analysis. Heterogeneity stemmed from varied MASLD diagnostic criteria [e.g., ultrasound, magnetic resonance imaging-proton density fat fraction (MRI-PDFF), biopsy], age ranges (3-19 years), and geographic settings. For example, global MASLD prevalence (13%) and prevalence in obese children (47%) varied due to diagnostic and population differences. Preliminary assessments showed high heterogeneity (I² > 75%). A random-effects model was considered for prevalence estimates but deemed unsuitable due to this variability. We grouped studies into epidemiology, pathophysiology, and clinical implications. We gave higher weight to RCTs and large cohort studies (NOS ≥ 7, low RoB 2). Smaller or lower-quality studies contextualized trends. This approach ensured a comprehensive synthesis while addressing evidence quality. The literature search and selection process are summarized in the PRISMA flowchart (Figure 1).

Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart of the literature selection process. RCT: Randomized controlled trial.

RESULTS

In this systematic review, 70 studies met the established inclusion and quality criteria. Among these, cohort studies accounted for 30 publications, RCTs comprised 25, and systematic reviews or meta-analyses made up the remaining 15. The research topics covered by these studies were varied: (1) 25 focused on epidemiological patterns and prevalence data of pediatric MASLD; (2) 20 explored pathophysiological mechanisms including hepatic insulin resistance and metabolic dysfunction; (3) 15 investigated diagnostic techniques and noninvasive biomarkers; and (4) 10 addressed clinical interventions and management strategies, including lifestyle and pharmacological approaches.

Significant prevalence gaps in pediatric MASLD underscore disparities across populations, with global prevalence ranging from 13% in children generally, escalating to 47% in obese youth, highlighting obesity as a key risk factor[1,13]. These gaps emphasize the urgent need for targeted screening in high-risk groups to curb early disease progression. Promising intervention programs have shown efficacy in addressing MASLD and related metabolic risks in at-risk pediatric populations. Lifestyle interventions, such as combined diet and exercise, have reduced liver fat by 8% in obese children with MASLD[14]. Low-sugar diets have effectively decreased hepatic fat in adolescents[15]. Pharmacological approaches, including glucagon-like peptide-1 (GLP-1) receptor agonists like liraglutide and semaglutide, have achieved significant reductions in BMI, liver fat, and metabolic markers, despite some gastrointestinal side effects[16,17]. Vitamin E supplementation, particularly tocotrienol-rich forms, has also improved liver steatosis and insulin levels, supporting its role as an adjunct to lifestyle changes[18,19].

Epidemiology of pediatric MASLD and youth-onset T2D

Global and regional prevalence of MASLD and obesity: The prevalence of MASLD in pediatric populations is closely linked to the ongoing global obesity epidemic. A systematic review and meta-analysis estimated that MASLD affects approximately 13% of children worldwide, with prevalence rising markedly to 47% among children with obesity[1]. Obesity – defined as a BMI at or above the 95^th percentile for age and sex – is considered the primary driver of hepatic steatosis in youth[20].

In the United States, approximately 19% of children aged 2-19 years are classified as obese. This burden is disproportionately higher among Hispanic (26%) and non-Hispanic Black (24%) children compared to their non-Hispanic White counterparts (16%)[21]. The prevalence of MASLD among obese children in the United States ranges from 30% to 50%, with elevated liver enzymes and ultrasound-detected hepatic steatosis commonly reported in this population[5].

The Middle East and North Africa (MENA) region has also experienced a sharp increase in pediatric obesity, largely driven by urbanization, dietary shifts, and sedentary behaviors. In Iran, the prevalence of childhood obesity in urban areas is estimated at 10%-15%, with MASLD reported in 20%-40% of obese children[22,23]. Furthermore, the International Diabetes Federation (IDF) has documented a 12.2% prevalence of adult diabetes in the MENA region, underscoring pediatric MASLD as a critical precursor to future metabolic disease[24].

In China, childhood obesity rates have risen substantially, reaching 15%-20% in urban regions. Among obese Chinese children, MASLD prevalence is estimated at 30%-50%, with particularly high rates observed in metropolitan areas such as Beijing and Shanghai[7].

In India, an estimated 8.4% of children aged 3-18 years are classified as obese, contributing to a MASLD prevalence of 35%-45% among obese youth. This high rate is attributed to both environmental influences and genetic predispositions, including variants in the patatin-like phospholipase domain-containing protein 3 gene[25,26].

Globally, the prevalence of childhood obesity has more than tripled since the 1970s, with an estimated 340 million children and adolescents classified as overweight or obese as of 2024[27]. MASLD prevalence varies widely by region, ranging from 10%-20% in general pediatric populations to 40%-70% among obese cohorts[1]. Figure 2 illustrates the global and regional distribution of childhood obesity and MASLD, highlighting their co-occurrence and the escalating public health burden they pose in pediatric populations.

Figure 2 Global and regional prevalence of childhood obesity and metabolic dysfunction-associated steatotic liver disease. MASLD: Metabolic dysfunction-associated steatotic liver disease.

Rising trends in youth-onset T2D: Once considered a rare condition, youth-onset T2D has emerged as a growing global health concern, largely driven by the rising prevalence of obesity and MASLD. The incidence of T2D among children and adolescents is increasing at an alarming rate, with pronounced geographic and ethnic disparities.

In the United States, the prevalence of youth-onset T2D nearly doubled between 2001 and 2017, rising from 0.34 per 1000 individuals to 0.67 per 1000 individuals aged 10-19 years – reflecting a 95% relative increase[5]. Roughly 75% of children diagnosed with T2D are classified as obese, and MASLD is reported in 30%-40% of these cases[6].

In MENA region, youth-onset T2D is also on the rise, particularly in urban environments. In Iran, incidence rates among adolescents range between 5 per 100000 and 10 per 100000, with higher frequencies observed among obese children with concurrent MASLD[28]. Comparable patterns have been documented in Saudi Arabia, where youth-onset T2D is strongly associated with MASLD and a family history of diabetes[29].

In China, prevalence rates of youth-onset T2D vary considerably, from 1.6 per 100000 to 15 per 100000, with urban centers such as Beijing and Shanghai reporting rates as high as 520 per 10000[2]. In India, the incidence of adolescent T2D is steadily increasing, particularly in urban areas where MASLD is increasingly identified as a major comorbidity. Recent estimates indicate that 10-20 per 100000 youths in these populations are affected[30].

According to the IDF, close to 1.1 million children and adolescents globally are currently living with T2D, with the greatest burden observed in low-income and middle-income countries, where the prevalence of both obesity and MASLD continues to climb[31]. A Swedish cohort study further revealed that obese adolescents with MASLD have a 2.7-fold higher risk of developing T2D by age 30 compared to those without MASLD[3].

Geographic and ethnic disparities in MASLD and T2D

The incidence and prevalence of MASLD and youth-onset T2D vary significantly across geographic regions and ethnic groups, shaped by a complex interplay of genetic susceptibility, environmental exposures, and socioeconomic determinants.

Ethnic variations: In the United States, Hispanic and non-Hispanic Black youth exhibit disproportionately higher rates of MASLD – affecting 40%-50% of obese individuals – and youth-onset T2D, with incidence rates ranging from 1 per 1000 to 2 per 1000. In contrast, non-Hispanic White youth present lower prevalence estimates, with MASLD affecting 20%-30% and T2D rates around 0.5 per 1000. In Asian populations, particularly among individuals of South Asian descent such as those from India, there is a well-documented genetic predisposition to both MASLD and T2D. This genetic risk is compounded by prevalent dietary patterns rich in refined carbohydrates and reduced levels of physical activity[32].

Geographic differences: High-income countries – including the United States and Saudi Arabia – report elevated rates of MASLD, primarily due to the widespread prevalence of obesity and sedentary lifestyles. Conversely, low-income and middle-income countries such as India and Iran are witnessing a rapid rise in MASLD and youth-onset T2D, largely attributable to urbanization, dietary transitions, and declining physical activity[1]. While rural areas in Asia and the Middle East currently report lower rates of both conditions, the incidence is increasing as these communities undergo lifestyle and nutritional shifts associated with modernization[7].

Economic burden of MASLD and youth-onset T2D

The economic burden associated with MASLD and youth-onset T2D is substantial, encompassing both direct healthcare expenditures – such as diagnostic testing, medical treatment, and hospital admissions – and indirect costs, including lost productivity and caregiver-related responsibilities.

In the United States, annual healthcare spending for pediatric obesity-related conditions, including MASLD and T2D, is estimated at $12-15 billion. Youth-onset T2D alone incurs an average annual cost of approximately $9000 per patient, primarily due to hospitalizations, insulin therapy, and acute complications such as diabetic ketoacidosis[33-35]. The economic impact of MASLD adds an additional $1-2 billion annually, with major cost contributors including liver biopsies, imaging, and long-term monitoring[36].

In Iran, the estimated annual cost of managing pediatric T2D ranges from $500 per patient to $1000 per patient, while MASLD-related expenditures – covering liver function tests and imaging – add an additional $200-500 per case[37]. Similarly, in Saudi Arabia, the public healthcare system incurs an annual per-patient cost of $1500-3000 for pediatric MASLD and T2D management[38].

In China, direct healthcare expenses for youth-onset T2D are estimated at $1000-2000 per patient per year, with MASLD-related diagnostics contributing an additional $300-600[7]. In India, where out-of-pocket healthcare spending is the norm, families report allocating 10%-20% of their annual income to managing youth-onset T2D, exacerbating existing socioeconomic inequalities[39].

Globally, the economic impact of pediatric obesity and its associated comorbidities – including MASLD and T2D – is projected to exceed $1 trillion by 2030. This projection reflects not only the increasing prevalence of these conditions but also their long-term complications, including cardiovascular disease and liver failure[40]. Early intervention strategies targeting MASLD and youth-onset T2D have been shown to reduce healthcare expenditures by 20%-30% through the prevention of disease progression to more advanced stages[36].

The global epidemiology of childhood MASLD and youth-onset T2D reflects a multifactorial interplay of obesity, genetic predisposition, and environmental factors, with distinct regional and ethnic disparities. High-burden regions – including the Middle East, Asia, and the United States – are particularly affected due to the rapid rise in pediatric obesity and the increasing adoption of sedentary, urbanized lifestyles. The significant economic burden of these conditions underscores the need for timely detection, targeted preventive efforts, and comprehensive public health strategies that address social determinants of health and improve access to pediatric screening services.

Tackling the rising trajectory of MASLD and T2D in youth will require coordinated global efforts focused on obesity prevention, as well as the development of age-appropriate diagnostic criteria and evidence-based management strategies. As shown in Figure 3, the global prevalence of adolescent obesity continues to rise, contributing significantly to the early onset of T2D in youth populations.

Figure 3 Rising global trends in adolescent obesity and its contribution to the increasing prevalence of youth-onset type 2 diabetes. T2D: Type 2 diabetes; T2DM: Type 2 diabetes mellitus.

Pathophysiological mechanisms linking MASLD to youth-onset T2D

Hepatic insulin resistance and lipotoxicity: In pediatric MASLD, hepatic steatosis contributes to insulin resistance through the accumulation of lipotoxic intermediates, particularly diacylglycerols and ceramides. These metabolites activate protein kinase C, which phosphorylates insulin receptor substrate (IRS) proteins, thereby disrupting downstream insulin signaling. This impairment attenuates the suppression of hepatic gluconeogenesis, leading to elevated glucose production and systemic insulin resistance – central features in the pathogenesis of youth-onset T2D[41-43]. Studies have demonstrated that obese children with MASLD exhibit significantly elevated hepatic ceramide levels, correlating with the severity of insulin resistance[44]. Moreover, this lipotoxic environment induces endoplasmic reticulum stress, further exacerbating hepatic dysfunction and promoting T2D progression[41].

Oxidative stress and amino acid metabolism: Oxidative stress plays a pivotal role in the pathogenesis of pediatric MASLD by contributing to hepatic injury and systemic metabolic dysfunction. Hepatocellular lipid overload overwhelms mitochondrial β-oxidation, leading to excessive production of reactive oxygen species (ROS). These ROS damage cellular structures, including mitochondrial membranes, DNA, and proteins, thereby impairing mitochondrial function and amplifying hepatic insulin resistance[45]. Concurrently, lipid peroxidation driven by ROS exacerbates inflammation and hepatocyte injury. Elevated serum levels of malondialdehyde, a marker of lipid peroxidation, have been reported in children with MASLD and are strongly associated with steatosis severity[38]. In addition, decreased activity of endogenous antioxidant enzymes such as glutathione peroxidase and superoxide dismutase is commonly observed, increasing susceptibility to oxidative injury[46]. This imbalance fosters a pro-inflammatory hepatic environment that accelerates MASLD progression and heightens T2D risk[46].

Alterations in amino acid metabolism further contribute to MASLD pathogenesis. Hepatic steatosis disrupts the metabolism of branched-chain amino acids (BCAAs) – leucine, isoleucine, and valine – resulting in their systemic accumulation. Elevated BCAA levels activate the mechanistic target of rapamycin signaling pathway, which inhibits IRS function and promotes hepatic insulin resistance and gluconeogenesis[47].

A cohort study showed that obese children with MASLD had significantly higher plasma BCAA concentrations than age-matched controls, with a positive correlation to intrahepatic fat content as measured by MRI-PDFF[47]. Moreover, disruptions in sulfur-containing amino acid metabolism, particularly involving methionine and cysteine, impair glutathione synthesis – a key antioxidant defense mechanism. This depletion further exacerbates oxidative stress and promotes hepatic inflammation[48]. Elevated homocysteine levels resulting from altered methionine metabolism have also been associated with endothelial dysfunction and increased cardiovascular risk in pediatric MASLD[48]. This evidence emphasizes the bidirectional relationship between metabolic and oxidative pathways.

The interplay between oxidative stress and altered amino acid metabolism generates a reinforcing feedback loop that accelerates MASLD progression. ROS-mediated mitochondrial dysfunction disrupts amino acid catabolism, while BCAA accumulation exacerbates insulin resistance and lipid deposition, further stimulating ROS production[45,47]. This cycle is particularly pronounced in children with visceral obesity. Interventions such as antioxidant supplementation and modulation of BCAA intake may represent promising strategies to mitigate MASLD severity and associated metabolic complications in pediatric populations[46,48].

Inflammatory cytokine signaling: Chronic low-grade inflammation is a hallmark of MASLD and a key contributor to insulin resistance and T2D development in children. In obese pediatric patients, dysfunctional adipose tissue secretes pro-inflammatory cytokines—including tumor necrosis factor-alpha, interleukin-6 (IL-6), and resistin – that impair hepatic insulin signaling and promote β-cell dysfunction[49]. These cytokines disrupt IRS phosphorylation and activate stress-associated kinases such as c-Jun N-terminal kinase and IκB kinase, thereby intensifying insulin resistance[49].

Additionally, hepatic Kupffer cells and infiltrating macrophages amplify the inflammatory cascade by releasing further cytokines, exacerbating liver injury and accelerating the transition from insulin resistance to overt diabetes[50]. Elevated IL-6 levels in children with MASLD have been strongly correlated with insulin resistance and pancreatic β-cell stress, highlighting the systemic impact of hepatic inflammation.

Gut-liver axis and microbiome dysbiosis: Mounting evidence supports the critical role of gut-liver axis dysregulation in pediatric MASLD. Disruption of intestinal barrier integrity facilitates the translocation of bacterial endotoxins – particularly lipopolysaccharide (LPS) – into the portal circulation. LPS activates hepatic toll-like receptors, initiating inflammatory signaling cascades that promote insulin resistance and hepatic injury[51].

Children with MASLD frequently exhibit distinct gut microbiota profiles characterized by reduced microbial diversity and increased abundance of LPS-producing bacteria, further aggravating hepatic inflammation[10]. Recent studies have shown that circulating LPS concentrations are elevated in affected children and positively correlate with hepatic steatosis severity and insulin resistance[52]. Targeting the gut-liver axis through probiotics, prebiotics, or dietary modification offers a promising therapeutic approach to restore microbial balance and attenuate MASLD progression in pediatric population[51]. Figure 4 depicts the primary pathophysiological mechanisms correlated between MASLD and youth-onset T2D.

Figure 4 Pathophysiological mechanisms underlying metabolic dysfunction-associated steatotic liver disease and youth-onset type 2 diabetes in pediatric populations. BCAA: Branched-chain amino acid; DAG: Diacylglycerol; IKK: IκB kinase; IL-6: Interleukin-6; IRS: Insulin receptor substrate; JNK: C-Jun N-terminal kinase; LPS: Lipopolysaccharide; MASLD: Metabolic dysfunction-associated steatotic liver disease; MDA: Malondialdehyde; mTOR: Mechanistic target of rapamycin; PK: Protein kinase; ROS: Reactive oxygen species; TNF-α: Tumor necrosis factor-alpha.

Psychological dimensions of pediatric MASLD, obesity, and youth-onset T2D

The increasing prevalence of MASLD, obesity, and youth-onset T2D in pediatric populations presents a multifaceted challenge with significant psychological implications. The bidirectional relationship between these metabolic conditions and mental health concerns accelerates disease progression and complicates management. This section explores the psychological dimensions of pediatric MASLD, obesity, and T2D, emphasizing the roles of stress, stigma, mental health comorbidities, and the potential benefits of psychological interventions.

Psychological stress and disease progression: Chronic psychological stress is a significant contributor to metabolic dysregulation in youth, primarily through activation of the hypothalamic-pituitary-adrenal axis, which elevates cortisol levels. This hormonal imbalance promotes visceral adiposity and hepatic lipid accumulation, both of which are characteristic features of MASLD and obesity[53]. Common stressors – such as academic pressures and socioeconomic hardship – can further impair insulin sensitivity, thereby increasing the risk of youth-onset T2D. A cohort study involving 900 obese adolescents found that those with high perceived stress had a 1.7-fold increased risk of impaired glucose tolerance compared to their less-stressed peers[54]. Stress-induced emotional eating, often involving energy-dense foods, contributes to the persistence and worsening of MASLD and obesity, reinforcing a vicious cycle of metabolic and psychological harm[55].

Stigma and emotional well-being: Emerging research underscores the detrimental psychological effects of obesity and its metabolic complications – including MASLD and T2D – on children and adolescents. A systematic review found a strong association between obesity and increased body dissatisfaction, alongside diminished self-esteem[56]. For instance, one study reported that 77% of obese adolescents experienced low self-esteem, while 64% faced bullying, indicating a substantial psychological burden[57].

During the COVID-19 pandemic, a cross-sectional study revealed that 41% of adolescents reported increased body dissatisfaction, particularly among those with elevated BMI[58]. The coexistence of MASLD in up to 70% of youth with T2D further illustrates the complex overlap between metabolic and emotional health issues[59].

Adolescents with T2D often experience heightened shame and anxiety, fueled by public misconceptions about the disease’s preventability. Compared to their peers with type 1 diabetes, these youth encounter unique psychosocial burdens that interfere with self-management and overall well-being. The stigma surrounding T2D significantly undermines treatment adherence and quality of life[60,61]. Therefore, implementing psychological support strategies that directly address stigma is essential for improving mental health and therapeutic outcomes.

Mental health comorbidities: Depression and anxiety are frequently reported among children with MASLD and T2D, partially driven by systemic inflammation. Elevated levels of pro-inflammatory cytokines, such as IL-6, have been shown to disrupt neurotransmitter systems and contribute to mood dysregulation[6]. A study involving 600 obese children with MASLD found that 22% met clinical criteria for depression, in contrast to only 8% of non-MASLD peers[62].

The daily psychological demands of T2D management – especially the fear of long-term complications – further elevate anxiety and adversely affect quality of life. These findings support the integration of psychological assessment into routine diabetes care to enhance overall outcomes[63]. Additionally, children diagnosed with attention deficit hyperactivity disorder (ADHD) are at increased risk for obesity and MASLD. One study reported that the prevalence of MASLD in youth with ADHD is nearly double that of those without the disorder, likely due to impulsive eating behaviors[64,65].

This overlap reinforces the necessity for coordinated strategies addressing behavioral and metabolic risk factors in children.

Psychological interventions: Recent evidence affirms the effectiveness of psychological interventions in improving both emotional and metabolic outcomes in youth affected by MASLD and T2D. Cognitive-behavioral therapy (CBT) has shown substantial benefit in reducing depressive symptoms and enhancing self-esteem in adolescents. A randomized controlled trial involving 110 adolescents with bulimia nervosa found that both CBT and family-based treatment significantly improved psychological well-being, with comparable outcomes between the two approaches[66].

Family-based therapy has also demonstrated efficacy in improving weight outcomes. An interventional study revealed a mean reduction of 0.14 in BMI z-scores after six months of family-centered care (P < 0.001)[67]. These programs emphasize parental involvement in lifestyle modification, which is a key factor in achieving sustainable pediatric weight management[68].

School-based mindfulness interventions offer scalable preventive strategies. These programs have been shown to reduce intake of sugar-sweetened beverages and improve stress management in school-aged children[69]. By fostering emotional regulation, mindfulness practices promote healthier eating habits and overall mental well-being[70].

Despite these promising findings, access to psychological care remains limited, particularly in low-resource settings. Families in such contexts often face greater risk yet receive inadequate support[71]. Other challenges include a shortage of pediatric-focused psychological services and persistent stigma surrounding mental health. Figure 5 demonstrates the psychological dimensions of pediatric MASLD and obesity, emphasizing the roles of stress, stigma, and their impact on disease progression and self-management.

Figure 5 Psychological factors influencing childhood metabolic dysfunction-associated steatotic liver disease, obesity, and youth-onset type 2 diabetes. T2D: Type 2 diabetes; MASLD: Metabolic dysfunction-associated steatotic liver disease; ADHD: Attention deficit hyperactivity disorder; ↓: Reduce.

Diagnostic challenges and emerging biomarkers in pediatric MASLD

Diagnosing MASLD in children presents considerable clinical challenges, primarily due to the asymptomatic nature of the early disease and the limited sensitivity and specificity of currently available diagnostic modalities. A significant proportion of pediatric cases remain undiagnosed until the disease has progressed to more advanced stages, often detected incidentally or after the onset of complications. Although liver biopsy is considered the diagnostic gold standard – offering definitive histological evaluation of steatosis, inflammation, and fibrosis – it is invasive, costly, and carries risks such as bleeding and infection, rendering it unsuitable for routine pediatric screening[72].

Routine liver enzyme assays, such as alanine aminotransferase (ALT) and aspartate aminotransferase, provide limited diagnostic value. ALT levels remain within normal limits in approximately 20%-30% of children with biopsy-confirmed MASLD, undermining its reliability as a screening biomarker[34]. Moreover, elevated transaminase levels are nonspecific and may be attributable to other hepatic or systemic conditions[73]. Abdominal ultrasound, although widely employed as a first-line imaging modality, lacks the resolution and specificity necessary to reliably differentiate between simple steatosis and more advanced liver pathology, such as steatohepatitis or fibrosis[74,75].

Given these limitations, growing research interest has turned toward the development and validation of non-invasive biomarkers for early detection and disease monitoring. Among these, adiponectin – an adipokine involved in glucose homeostasis and fatty acid oxidation – has emerged as a promising candidate. Its levels are consistently reduced in children with MASLD and inversely correlate with hepatic fat accumulation and inflammatory activity[34,76]. High-sensitivity C-reactive protein, a systemic marker of inflammation, is also elevated in obese children with hepatic steatosis, suggesting a link between inflammatory burden and disease progression[44]. Cytokeratin-18 (CK-18), a fragment derived from hepatocyte apoptosis, has demonstrated potential in distinguishing simple steatosis from metabolic dysfunction-associated steatohepatitis, thereby aiding in the stratification of disease severity[77-79].

Innovations in imaging techniques further enhance the diagnostic toolkit. Vibration-controlled transient elastography (FibroScan) offers a non-invasive, well-tolerated method for assessing liver stiffness and has shown strong concordance with biopsy-confirmed fibrosis in pediatric cohorts[80]. MRI-PDFF enables accurate quantification of hepatic fat and is valuable for longitudinal monitoring, although its high cost and limited availability may hinder broader clinical implementation[74,81].

Despite advancements in biomarkers and imaging, the absence of standardized diagnostic criteria for MASLD in children continues to hinder early identification and consistent monitoring. Integrative diagnostic strategies – combining blood-based markers, advanced imaging modalities, and emerging technologies such as amino acid profiling, lipidomics, and machine learning – represent promising directions for enhancing diagnostic accuracy and facilitating personalized disease management in pediatric populations[34]. Table 2 summarizes the comparative diagnostic applications of conventional serum biomarkers and emerging non-invasive tools in pediatric MASLD[44,72,73,80-88]. Table 3 summarizes the studies on pediatric MASLD, obesity, and youth-onset T2D[1,3,4,13-19,48,72,80,81,89-94].

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.

Interventions in pediatric MASLD and T2D

The rising prevalence of MASLD among children and adolescents underscores the urgent need for early preventive strategies to mitigate long-term health consequences. These interventions should primarily target modifiable risk factors such as excessive free sugar intake, physical inactivity, and increasing pediatric obesity rates[95]. Evidence suggests that reducing dietary free sugar intake can significantly lower hepatic fat content in adolescents with MASLD[15]. In addition, structured lifestyle interventions focused on nutrition and physical activity have demonstrated efficacy in managing pediatric obesity and associated liver complications, as supported by findings from ongoing RCTs[96].

Nutritional interventions are a cornerstone of MASLD prevention in pediatric populations. Diets abundant in fruits, vegetables, whole grains, and omega-3 fatty acids have been linked to reductions in hepatic steatosis and improved liver outcomes[46]. Conversely, high consumption of fructose, saturated fats, and ultra-processed foods has been strongly associated with the pathogenesis of MASLD, largely due to their role in promoting hepatic lipid accumulation and insulin resistance[44]. Importantly, nutrition education programs that involve both children and caregivers – particularly when implemented through school-based curricula and primary care – have proven effective in establishing and sustaining healthy eating behaviors[95].

Physical activity is another essential pillar in the prevention and management of MASLD in youth. Current pediatric guidelines recommend at least 60 minutes of moderate to vigorous physical activity daily to promote metabolic health, reduce visceral adiposity, and support liver function[96]. Recent clinical trials have demonstrated that structured exercise regimens, especially when combined with behavioral counseling, result in significant improvements in liver enzyme profiles, insulin sensitivity, and overall cardiometabolic health in children with MASLD[96].

Public health policies play a crucial role in addressing broader, systemic contributors to pediatric obesity and MASLD. For example, Mexico’s implementation of an 8% tax on energy-dense foods led to a 12% decline in sugary beverage purchases over two years[96]. Likewise, front-of-package nutritional warning labels and restrictions on marketing unhealthy food to children have been associated with healthier dietary choices and reduced obesity risk in regions such as the Middle East and China[97].

Sustained lifestyle change requires coordinated efforts across family and community settings. Parental involvement in dietary and physical activity programs significantly enhances adherence among children and fosters healthier behaviors, particularly during early childhood[3]. Community-based approaches – including school wellness initiatives, improvements in local food environments, and the development of national guidelines on nutrition and physical activity – should be prioritized to address the upstream determinants of pediatric obesity and MASLD[97].

Despite these promising strategies, inequities in policy implementation remain a substantial barrier. High-risk ethnic groups and populations in resource-limited settings often lack access to preventive services, thereby exacerbating health disparities. Contributing factors include limited availability of healthy foods in underserved areas, inadequate physical education infrastructure in schools, and insufficient training among pediatric healthcare providers in lifestyle counseling[96]. To overcome these obstacles, multidisciplinary and coordinated approaches are required to integrate MASLD prevention into routine pediatric care and broader public health strategies. Figure 6 summarizes key preventive strategies for pediatric MASLD and T2D.

Figure 6 Preventive strategies for pediatric metabolic dysfunction-associated steatotic liver disease and youth-onset type 2 diabetes. MASLD: Metabolic dysfunction-associated steatotic liver disease; T2D: Type 2 diabetes.

Contemporary therapeutic approaches to pediatric MASLD

The effective management of MASLD in children requires a comprehensive, multifaceted approach that emphasizes sustainable lifestyle changes, early risk stratification, and the development of pediatric-specific clinical guidelines. Currently, lifestyle modification remains the cornerstone of treatment. Interventions targeting nutrition, physical activity, and behavioral changes have demonstrated measurable improvements in hepatic steatosis, insulin sensitivity, and cardiometabolic risk profiles in pediatric populations[95,98].

Dietary modification is central to MASLD management. Reducing free sugar intake – particularly fructose from sugar-sweetened beverages – is strongly associated with decreased intrahepatic lipid accumulation and improved liver enzyme levels. RCTs have shown that adolescents adhering to a low free sugar diet experience significant reductions in liver fat and inflammatory markers[15]. Additionally, Mediterranean-style diets – rich in monounsaturated fats, dietary fiber, and omega-3 fatty acids – have been linked to improved hepatic steatosis and favorable metabolic outcomes[99].

Physical activity interventions are equally vital. Current pediatric guidelines recommend a minimum of 60 minutes of moderate to vigorous physical activity per day. Structured exercise programs, incorporating both aerobic and resistance training, have been shown to reduce hepatic fat content and enhance insulin sensitivity in obese children with MASLD[95]. Family engagement significantly enhances adherence and long-term success, especially when interventions are integrated into school and community-based programs[95].

Pharmacologic treatment options for pediatric MASLD are currently limited, with no medications formally approved for this population. However, several agents have shown potential in clinical studies. Vitamin E has demonstrated histological improvement in selected cases, particularly among non-diabetic children with biopsy-confirmed steatohepatitis, though concerns remain regarding its long-term safety[100]. Metformin has shown modest benefits in metabolic parameters, while GLP-1 receptor agonists – such as liraglutide and semaglutide – have demonstrated promising effects in reducing hepatic fat and improving metabolic markers in adolescents with obesity. Nevertheless, their use in MASLD remains off-label and requires further validation[16,17].

A personalized treatment approach tailored to patient-specific factors such as age, sex, genetic predisposition, and comorbidities (e.g., insulin resistance, dyslipidemia) is essential to optimize outcomes. Multidisciplinary care – led by pediatric hepatologists, endocrinologists, dietitians, and behavioral health specialists – is crucial for long-term disease management. Additionally, non-invasive tools such as transient elastography and serum biomarkers (e.g., CK-18, adiponectin) facilitate early detection of disease progression and timely intervention[74,80].

Ultimately, the integration of individualized lifestyle modifications, cautious pharmacologic intervention, and family-centered, multidisciplinary care represents the most effective strategy for managing MASLD in children.

DISCUSSION

This study aimed to comprehensively examine the interplay between MASLD, obesity, and early-onset T2D, focusing on epidemiology, pathophysiology, prevention, and management strategies. The findings align with existing literature, highlighting the rising prevalence of MASLD in pediatric populations – particularly among children with obesity – and its pivotal role in promoting insulin resistance and increasing the risk of developing T2D.

Epidemiological evidence confirms a strong association between pediatric MASLD and obesity, reinforcing prior studies that identify obesity as the principal driver of hepatic steatosis in children[1,3]. The high prevalence of MASLD in obese youth underscores the urgent need for early identification and intervention, given its established link with an elevated risk of T2D and cardiovascular complications[8,9].

Pathophysiological insights reveal that hepatic insulin resistance, mitochondrial dysfunction, and chronic inflammation are key mechanisms underlying MASLD progression and its metabolic consequences. These processes are exacerbated by gut microbiota dysbiosis, which contributes to systemic inflammation and impaired glucose metabolism. This multifactorial pathogenesis highlights the bidirectional relationship between MASLD and T2D, emphasizing the importance of comprehensive, multifaceted treatment approaches[49,51].

Despite recent advances, significant challenges persist in preventing and managing pediatric MASLD. Socioeconomic disparities limit access to healthy food options and structured physical activity programs, while gaps in provider training hinder the delivery of effective, child-specific lifestyle counseling. These barriers underscore the need for coordinated multidisciplinary interventions and public health policies tailored to at-risk pediatric population[95,101].

Study limitations

Despite the comprehensive scope of this review, several important limitations should be acknowledged. Firstly, most of the included studies predominantly focus on adult populations, thereby limiting the generalizability of their findings to children and adolescents. Pediatric-specific data on the progression of MASLD – particularly in relation to its interaction with obesity T2D – remain limited, especially with regard to longitudinal outcomes. Secondly, the absence of standardized diagnostic criteria for pediatric MASLD complicates cross-study comparisons and impedes early disease identification[72]. Thirdly, the long-term economic and metabolic consequences of MASLD in youth are not well characterized, as most cost-effectiveness evaluations are extrapolated from adult data[48].

Furthermore, high-risk ethnic groups – such as Hispanic, South Asian, and Indigenous populations – are significantly underrepresented in clinical trials and observational studies. This underrepresentation perpetuates disparities in care delivery and limits the applicability of findings to diverse populations[34]. Lastly, although emerging biomarkers such as adiponectin and CK-18 show promise for early diagnosis and disease monitoring, their clinical utility in pediatric MASLD remains to be validated.

Research gaps and future directions

Despite increasing recognition of pediatric MASLD as a critical global health concern, significant research gaps continue to hinder progress in its diagnosis, treatment, and long-term management. One of the most pressing limitations is the scarcity of longitudinal studies tracking the natural history of MASLD from childhood into adulthood. Most existing data are cross-sectional, which limits understanding of disease progression – particularly the transition from simple steatosis to more advanced stages such as fibrosis and cirrhosis in pediatric population[95,96].

A major diagnostic challenge is the absence of validated, age-specific criteria. Current definitions are frequently extrapolated from adult guidelines and fail to capture the distinct histopathological and metabolic profiles observed in children. Moreover, many non-invasive tools lack the sensitivity to detect early-stage steatohepatitis or to differentiate it from simple steatosis in pediatric cases. Although advanced imaging modalities such as MRI-PDFF and transient elastography offer promising results, their high cost and limited accessibility hinder widespread implementation in low-resource settings[65,73].

Therapeutic research in pediatric MASLD remains underdeveloped. Lifestyle modification is the mainstay of treatment, but its effectiveness varies across subgroups. Pharmacologic trials targeting MASLD in children are scarce, and most agents – including GLP-1 receptor agonists and farnesoid X receptor agonists – have been studied predominantly in adult populations. There is a clear need for pediatric-specific clinical trials with endpoints tailored to the biological and clinical features of MASLD in children[65,83].

In addition, the influence of socioeconomic and ethnic disparities on MASLD prevalence and outcomes remains insufficiently explored. Hispanic, South Asian, and Indigenous youth may be at greater risk due to complex interactions between genetic predisposition and environmental exposures, yet they are consistently underrepresented in clinical research. Furthermore, the role of social determinants of health – such as food insecurity, limited healthcare access, and parental education – on disease progression and treatment adherence is poorly characterized[18,41].

Future research priorities should include the development of pediatric-specific diagnostic algorithms, validation of reliable non-invasive biomarkers, and advancement of targeted pharmacologic therapies. Longitudinal cohort studies are essential to clarify disease trajectories and to identify children at highest risk for progressive liver damage. Moreover, integrating health equity frameworks and precision medicine approaches will be critical to ensuring that emerging diagnostic and therapeutic advances are equitably accessible across all pediatric populations.

Culturally sensitive, age-appropriate interventions should also be developed and evaluated through well-designed longitudinal studies that consider both metabolic and psychological outcomes. Incorporating psychological care into routine pediatric practice is essential for a holistic approach to managing MASLD, obesity, and T2D in youth.

CONCLUSION

Pediatric MASLD is a critical component of the global childhood obesity epidemic. It significantly contributes to youth-onset T2D. This review highlights its multifactorial pathogenesis, including hepatic steatosis, insulin resistance, inflammation, and socioeconomic factors. Shared risk factors suggest MASLD actively drives diabetes in youth.

Despite progress, challenges persist. These include the lack of pediatric-specific diagnostic criteria, limited longitudinal data, and scarce pharmacological options. Lifestyle modification remains central, but structural barriers hinder implementation. Early screening tools, personalized interventions, and equitable public health policies are essential. Promising therapies, like GLP-1 receptor agonists, require further pediatric trials. Addressing socioeconomic and ethnic disparities through culturally sensitive, equity-focused strategies is critical to reversing trends and improving outcomes in at-risk youth.