Fighting the epidemic of pediatric metabolic dysfunction-associated steatotic liver disease: Role of non-invasive diagnostics and early pharmacological intervention

Abstract

The global rise in childhood obesity has made metabolic dysfunction-associated steatotic liver disease (MASLD) the leading cause of pediatric liver disease. Studies have consistently reported alarmingly high rates of advanced fibrosis in up to 20% of adolescents with MASLD. There is evidence that pediatric MASLD may run a more severe clinical course compared to adults, as well as pose an independent risk factor for mortality than pediatric obesity or type 2 diabetes mellitus alone. This underscores the necessity for timely recognition, accurate diagnosis and early institution of therapeutic interventions for pediatric MASLD. In this minireview, we discuss the various non-invasive diagnostic modalities used for the evaluation of MASLD, and propose an updated diagnostic and monitoring algorithm incorporating recent multi-societal statements. The advent of non-invasive diagnostics such as vibration-controlled transient elastography in children allows for earlier recognition of liver fibrosis, and may prioritize the need for early pharmacological therapy. We also discuss the importance of early pharmacological intervention in pediatric MASLD, in particular the use of glucagon-like peptide 1 receptor agonists which may have potential to halt MASLD progression if instituted early, and the potential role for novel anti-fibrotic therapy in this population.

Key Words: Pediatric metabolic dysfunction-associated steatotic liver disease; Glucagon-like peptide 1 receptor agonists; Vibration-controlled transient elastography; Resmetirom; Pediatric obesity

Core Tip: The escalating prevalence of pediatric metabolic dysfunction-associated steatotic liver disease (MASLD) mirrors the rise in pediatric obesity. The advent of non-invasive diagnostics may allow for earlier recognition of liver fibrosis, and may prioritize the need for early pharmacological therapy. We propose an updated diagnostic and monitoring algorithm incorporating recent multi-societal statements in pediatric MASLD. The increased use of weight-loss pharmacotherapy such as glucagon-like peptide 1 receptor agonists in adolescent patients has shown efficacy in inducing weight loss, which may have potential in halting MASLD progression if instituted early in the disease course.

INTRODUCTION

The incidence of pediatric obesity and commonly associated pediatric metabolic dysfunction-associated steatotic liver disease (MASLD) have reached epidemic proportions. Although geographic variation in regional prevalences - 8.53% in North America and 7.01% in Asia, and a 52.49% prevalence in children with overweight or obesity[1] is noted, within Asia, a meta-analysis of mainland Chinese children reported a 43% prevalence of MASLD amongst children with overweight and obesity[2]. Eslam et al[3,4] first proposed a consensus-driven change in nomenclature of non-alcoholic fatty liver disease (NAFLD) to metabolic (dysfunction) associated fatty liver disease (MAFLD), followed by an updated 2023 consensus statement[5] to replace the stigmatizing term ‘fatty’ with ‘steatotic’ in the current nomenclature of MASLD. This change has been generally accepted in the adult and pediatric populations in recognition of the central role of metabolic-dysregulation in the underlying pathophysiology of this condition, and the metabolic risk factors associated with it[3,6,7]. Importantly, the rising prevalence of pediatric obesity has led to a parallel increase in the prevalence of pediatric MASLD. In fact, MASLD is now recognized as one of the most common causes of chronic liver disease affecting children and adolescents[8]. Timely recognition and therapeutic intervention for pediatric MASLD is urgently needed.

METHODOLOGY

Search strategy

This narrative review was performed through a literature review on PubMed, where articles published between the years 2000 to 2025 were identified using the key concepts of “pediatric” AND “MASLD or MAFLD or NAFLD or steatohepatitis or steatosis or fatty liver disease”. The articles summarized in the review included those that pertained to non-invasive diagnostics and pharmacotherapy in the pediatric age group. Only English language studies were included.

Definitions

The current working definition of pediatric MASLD is based on the updated 2023 multi-society Delphi consensus statement[5] to the above-mentioned 2021 consensus by Eslam et al[3], followed by a pediatric multi-societal statement of endorsement[9]: Biochemical/radiological/histopathological evidence of hepatic steatosis with one or more of 5 cardio-metabolic criterion: (1) Body mass index (BMI) ≥ 85^th percentile for age/sex (BMI z-score ≥ +1) or waist circumference > 95^th percentile or ethnicity adjusted with or without; (2) Fasting serum glucose ≥ 5.6 mmol/L or serum glucose ≥ 11.1 mmol/L or 2 hour post-load glucose levels ≥ 7.8 mmol/L or glycated hemoglobin ≥ 5.7% or existing/diagnosed/currently-treated type 2 diabetes mellitus (T2DM) or treatment for T2DM; (3) Hypertension: Blood pressure ≥ 95^th percentile or ≥ 130/80 mmHg whichever is lower for age < 13 years; age > 13 years: 130/80 mmHg or antihypertensive drug treatment; (4) Plasma triglycerides ≥ 1.15 mmol/L (age < 10 years); ≥ 1.7 mmol/L (age ≥ 10 years) or lipid-lowering treatment; and (5) Plasma high density lipoprotein cholesterol ≤ 1.0 mmol/L or lipid-lowering treatment.

However, as pediatric obesity and its metabolic complications become more prevalent, it is possible that children with MASLD may also have co-existing etiologies for steatotic liver disease i.e., ‘MASLD overlap’. The pediatric multi-societal statement particularly emphasizes that pediatric MASLD should only be diagnosed after alternate differential diagnoses are excluded with first-line investigations[9].

MASLD is considered an umbrella term to encompass the entire spectrum of steatotic liver disease associated with metabolic dysregulation - simple steatosis (> 5% hepatocytes with fat infiltration), steatohepatitis to steatofibrosis and cirrhosis. Metabolic dysfunction-associated steatohepatitis (MASH) is a subset of MASLD in which there is active hepatitis and inflammation-driven liver injury (hepatocyte ballooning, lobular inflammation, apoptosis etc.) and fibrosis.

Differences between pediatric and adult MASLD

Studies have consistently shown alarmingly high rates of advanced fibrosis in adolescents with MASLD, where 10%-20% of patients in tertiary care settings have advanced fibrosis[10]. In addition, there is suggestion that children with MASLD may run a more severe clinical course and be at higher risk for liver damage than adults[11]. This is due to histopathological differences in pediatric MASLD, in which portal inflammation is more predominant[12] and this predilection for portal/periportal hepatitis predisposes to higher rates of advanced fibrosis[13]. In contrast, adult-type MASLD is characterized by more hepatocyte ballooning injury and a higher prevalence of peri-sinusoidal zone 3 fibrosis[12].

The early onset of chronic liver disease means children are at risk for liver-related adverse events over a longer duration than adults: MASLD is now the fastest growing cause of liver cancer in adults[14], and may independently increase the risk for early-onset cancers[15]. A recent longitudinal study of 1096 children with MASLD showed a 40 times higher mortality risk than age- and sex-matched peers on long-term follow-up, with nearly half of the premature deaths accounted by liver-related events[16]. An individual’s predisposition to liver fibrosis and liver damage from MASLD is also likely influenced by a multitude of host and environmental factors: Certain genetic factors e.g., the I148M polymorphism in PNPLA3 gene confers a predilection for liver damage early in life from MASLD, and is of highest prevalence in the Hispanic population[17]. Environmental exposures to ‘endocrine disrupting chemicals’ and gut dysbiosis are also proposed mechanisms that perpetuate a state of chronic low-grade inflammation favoring insulin resistance and MASLD[18]. A composite predictive model combining both clinical risk factors and a polygenic risk score for MASLD may allow one to risk-stratify patients of highest risk of disease progression[19], but such models have not been validated in pediatric populations to date.

While clinical criteria for the diagnosis of MASLD has been outlined in multiple consensus statements, there remains a diagnostic gap for the spectrum of MASLD. The gold standard for the diagnosis of steatosis, steatohepatitis, fibrosis and cirrhosis is ultimately through liver histological examination, but the invasive nature of liver biopsies may make this unacceptable to patients and caregivers. Non-invasive diagnostic strategies for the spectrum of pediatric MASLD would therefore be welcomed in supporting clinicians who manage these children. These non-invasive modalities can also potentially be utilized in the surveillance and monitoring of treatment outcomes in MASLD.

Aims of this minireview

In this minireview, we discuss the various non-invasive diagnostic modalities used for the evaluation of MASLD, and propose an updated diagnostic and monitoring algorithm incorporating recent multi-societal statements. We also discuss the importance of early pharmacological intervention in pediatric MASLD, in particular the use of glucagon-like peptide 1 receptor agonists (GLP-1RA) which may have potential to halt MASLD progression if instituted early, and the potential role for novel anti-fibrotic therapy in this population.

NON-INVASIVE DIAGNOSTICS FOR PEDIATRIC MASLD

We discuss below the non-invasive diagnostics for pediatric MASLD. The diagnostic accuracies of the tests performed in pediatric MASLD cohorts, unless stated otherwise, are summarized in Table 1[20-29].

Table 1 Diagnostic accuracy of non-invasive diagnostics in pediatric metabolic dysfunction-associated steatotic liver disease.

Diagnostic		Sensitivity	Specificity	AUROC	Comparison	Ref.
Serum ALT ≥ 50 (boys) ≥ 44 (girls) in overweight children ≥ 10 years		0.88	0.26	-	Biopsy-proven NAFLD	Schwimmer et al[28], 2013
Serum ALT ≥ 80 in overweight children ≥ 10 years		0.57	0.71	-	Biopsy NAFLD	Schwimmer et al[28], 2013
		0.61	0.62	-	Biopsy NASH
		0.76	0.59	-	Biopsy advanced fibrosis
Serum ALT ≥ 26 (boys) ≥ 22 (girls)		0.53	0.69	0.66	Ultrasound-detected steatosis + metabolic risk factors	Di Bonito et al[21], 2025
PNFS		0.97 (cutoff > 8%)	0.33 (cutoff > 8%)	0.74	Biopsy (advanced fibrosis ≥ F3)	Alkhouri et al[20], 2014
Ultrasonography		0.60-0.65	-	-	Biopsy mild steatosis (5%-33%; adult data)	Ferraioli et al[22], 2019
		0.84	0.93	0.93	Moderate-severe steatosis (20%-30%; adult data)	Hernaez et al[23], 2011
TE-CAP		0.86	0.88	0.94	Biopsy/MRS S1-S3 steatosis	Jia et al[25], 2021
TE-CAP		0.89	0.90	0.95	Biopsy, imaging or MRI-PDFF	Xu et al[29], 2025
TE-LSM	> 7.4 kPa	1.00	0.92	0.99	Biopsy-proven significant fibrosis (≥ F2)	Nobili et al[26], 2008
	> 10.2 kPa	1.00	1.00	1.00	Biopsy: Advanced fibrosis (≥ F3)
	> 8.5 kPa	0.72	0.62	0.76	Advanced liver disease on biopsy (MASLD subset of larger pediatric cohort of CLD)	Jarasvaraparn et al[24], 2025
MR elastography (cut-off 3.05 kPa)		0.50	0.92	0.92	Biopsy (advanced fibrosis ≥ F3 vs F0-F2)	Schwimmer et al[27], 2017
MRI-PDFF		0.95	0.92	0.96	Biopsy/MRS S1-S3 steatosis	Jia et al[25], 2021

ALT: Alanine aminotransferase; AUROC: Area under receiver operating characteristic curve; CLD: Chronic liver disease; NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis; TE-CAP: Transient elastography-controlled attenuation parameter; TE-LSM: Transient elastography-liver stiffness measurement; MRI-PDFF: Magnetic resonance imaging-proton density fat fraction; MRS: Magnetic resonance spectroscopy; PNFS: Pediatric non-alcoholic fatty liver disease fibrosis score; MASLD: Metabolic dysfunction-associated steatotic liver disease.<br/>.

Blood biomarkers and scoring indices

Serum alanine aminotransferase: Serum transaminases have been the main screening tool for MASLD in children with obesity, with a typical pattern of alanine aminotransferase (ALT) elevation more than aspartate aminotransferase (AST). Concomitant elevation in gamma glutamyl transferase (GGT) and AST may predict more severe histopathological features[28]. Additionally, a recent adult cohort study showed a cholestatic biochemical pattern of MASLD, defined by ALT:alkaline phosphatase (ALP) ratio of less than 2, had poorer outcomes in terms of liver decompensation events and mortality than the hepatocellular pattern[30]. This suggests the importance of examining all biochemical indices of the liver function test, rather than serum ALT alone.

There are variations in ALT thresholds in the diagnosis of MASLD. The North American Society of Pediatric Gastroenterology, Hepatology and Nutrition 2017 NAFLD guidelines quote normal cut-offs of 22 mg/dL for girls and 26 mg/dL for boys, and the use of two times the gender-specific ALT (ALT ≥ 50 in boys, ≥ 44 girls) in overweight children with a sensitivity of 88% and specificity of 26% for the diagnosis of MASLD[31]. The European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) 2012 guidelines recommend similar cut-off values and propose a combination of serum ALT and ultrasonography to diagnose MASLD. While the serum ALT is a convenient and reasonably valid biomarker of monitoring improvement in MASLD[32], a meta-analysis estimates 25% of MASLD patients have a normal serum ALT[33]. Ciardullo et al[34] reported that only 41.4% of adolescents with advanced steatosis had elevated ALT levels, while 78% of those with significant fibrosis had normal ALT levels.

Prediction scoring indices: Several scoring indices for MASLD have been developed based on a composite of anthropometric measurements and serum biomarkers. The fatty liver index combines waist circumference, triglycerides, body-mass index and serum GGT, and has modest diagnostic accuracy in pediatric validation studies [area under curve (AUC) = 69.2%-71%][35,36]. Alkhouri et al[20] discussed the development of the pediatric NAFLD fibrosis score (PNFS) to improve the diagnostic accuracy of pre-existing fibrosis predictive tools, based on ALT, ALP, platelet counts and GGT, with similarly modest results (AUC = 74.0%)[20]. A more recent study of 457 European children with biopsy-proven NAFLD, led by the ESPGHAN fatty liver special interest group, showed that none of the established fibrosis scores (including the abovementioned PNFS) were able to accurately distinguish any presence of fibrosis from no fibrosis, nor provide any diagnostic advantage over serum ALT alone[37]. A 2021 systematic review of 16 pediatric studies of fibrosis tests in MASLD concluded that imaging techniques such as vibration-controlled transient elastography (VCTE) and ultrasound elastography were superior than prediction scores for most grades of biopsy-proven fibrosis[38]. The poor diagnostic accuracy of prediction scores could be due to the indirect nature of prediction scores utilizing non-specific clinical covariates and biomarkers, and the potential for extra-hepatic factors to influence serum biomarkers, such as the effect of systemic inflammation on platelet count.

Imaging modalities

Ultrasound: The comprehensive prevention project for overweight and obese adolescents study from China defined hepatic steatosis based on sonographic criteria of at least two features of the following: Diffusely increased hepatic echogenicity greater than kidney or spleen, vascular blurring and/or deep signal attenuation[39]. Abdominal sonography is poorly sensitive in milder degrees of hepatic steatosis (< 20%), and also cannot reliably distinguish between steatosis, steatohepatitis and fibrosis[40] until definite features of established cirrhosis have occurred i.e., coarsened hepatic echotexture and splenomegaly. Moreover, increased hepatic echogenicity may occur with other causes of hepatitis and infiltration of other substances (e.g., glycogen)[9]. The ESPGHAN 2012 guidelines recommend combining ultrasonography and serum aminotransferase testing in all children with obesity[41].

VCTE: The limitations of standard abdominal sonography have led to the advent of newer ultrasound-based modalities to measure liver stiffness and better distinguish steatosis from fibrosis. Shear-wave elastography techniques, such as VCTE and acoustic radiation force impulse techniques, involve the generation of shear waves in the liver. The measurement of shear wave speed is thereafter used to define liver stiffness as a surrogate measurement of fibrosis[42]. VCTE, commercially marketed as Fibroscan^®, has excellent diagnostic accuracy in detecting advanced hepatic fibrosis with a wealth of supporting evidence in the adult population[43]. VCTE consists of two distinct parameters: Controlled attenuation parameter (CAP) as a measure of steatosis based on the rapid attenuation of ultrasound waves in a steatotic liver; and liver stiffness as a measure of fibrosis. To date, VCTE imaging offers the best balance between diagnostic accuracy, cost-effectiveness and logistical convenience in the assessment of liver fibrosis/steatosis. It is increasingly utilized in children across a variety of hepatic indications: Chaidez et al[44] demonstrated excellent correlation between CAP and histologic steatosis grade, and a reasonably good discriminatory ability of the Fibroscan^®-AST score in biopsy-proven pediatric MASLD. The FORCE (Fibroscan^® in pediatric cholestatic liver disease) study across 13 North American pediatric centers prospectively analyzed serial changes in liver stiffness measurements (LSMs) in children with chronic liver disease (biliary atresia, Alagille etc.): There was good feasibility in obtaining LSMs in children above 2 years with good correlation to liver parameters and degree of portal hypertension[45].

Specific limitations in pediatrics include a wider variation of body habitus, influencing the skin-to-liver capsule distance and the choice of probe size (S pediatric probe, standard M probe, XL probe). Exact pediatric cut-off norms in VCTE parameters are still not well-established and there are slight variations between existing pediatric publications, possibly influenced by patient factors (age, habitus) and probe size. VCTE data from 867 adolescents in the National Health and Nutrition Examination Survey 2017-2018 defined the cut-off threshold for any degree of steatosis as median CAP ≥ 248 dBm and significant fibrosis (≥ F2) as liver stiffness ≥ 7.4 kPa[34]. The systematic review by Draijer et al[38] noted excellent diagnostic accuracy (AUC near 1.0) for significant fibrosis (≥ F2) based on two liver stiffness cut-offs (8.2 kPa with S-probe[46] and 7.4 kPa with M-probe[26]) in two separate studies by Alkhouri et al[46] and Nobili et al[26] respectively. We await the results of the pediatric LiverKids study of a large cohort of 2866 subjects between 9-16 years, in which the investigators aim to determine the prevalence of significant fibrosis based on a LSM of ≥ 6.5 kPa and that of NAFLD based on CAP ≥ 225 dBm[47].

Magnetic resonance imaging: Magnetic resonance elastography (MRE) is considered the most accurate non-invasive modality for liver fibrosis, similarly based on the generation of mechanical shear waves in the liver as with sonographic techniques. MRE has obvious advantages to sonographic shear wave techniques in patients with extremely large habitus and/or concomitant ascites. Magnetic resonance imaging-proton density fat-fraction liver mapping (MRI-PDFF) is a fat quantitative technique based on the differential proton signals in mobile water and visceral fat content, and accurately quantify fat across the entire liver as opposed to liver biopsies[48]. The broader utilization of MRE and MRI-PDFF is limited in the pediatric population due to the high cost, possible need for general anesthesia in an uncooperative child and need for expert radiologist analysis.

UTILITY OF NON-INVASIVE DIAGNOSTICS IN MONITORING THERAPEUTIC RESPONSE

The discussion in the earlier section had centered upon the utility of non-invasive modalities in the accurate diagnosis of fibrosis/steatosis in children; there exists very limited pediatric data on the utility of these modalities for monitoring therapeutic response. A common and reasonable target is the normalization of serum ALT within pediatric norms, despite serum ALT being an imperfect biomarker of therapeutic response[32]. Data from the pediatric FORCE dataset suggests that Fibroscan^® is a reasonably good and feasible alternative to liver biopsy in monitoring serial disease progression for pediatric chronic liver disease[45] and may be potentially useful in monitoring therapeutic response once pediatric cut-offs are well-established.

It is also important to establish appropriate follow-up time-intervals for each non-invasive modality to detect clinically significant changes. The performance of MRI-PDFF and VCTE was explored in the recent phase 3 MAESTRO-NASH trial[49], which incorporated these non-invasive modalities alongside biopsy-proven endpoints in adults with MASLD. In this trial, resmetirom treatment was associated with a ≥ 30% reduction in liver fat by MRI-PDFF, which showed a strong association with histological improvement, including resolution of steatohepatitis and improvement in fibrosis stage. In contrast, transient elastography (VCTE) did not demonstrate a statistically significant reduction in liver stiffness from baseline to week 52 across all arms; however, a trend toward reduced stiffness was noted in the higher-dose resmetirom group[49]. These findings suggest that MRI-PDFF may be a more sensitive early marker of therapeutic response than VCTE, particularly for capturing improvements in steatosis and early inflammatory changes.

Proposed algorithm for diagnosis and monitoring pediatric MASLD

We propose a management algorithm (Figure 1) based on the updated 2023 multi-societal consensus on MASLD[5] and the pediatric multi-societal statement in 2024[9], with a particular emphasis on the need to exclude alternate etiologies especially in the very young and lean MASLD. We also propose a combined diagnostic approach akin to that proposed in the ESPGHAN 2012 pediatric MASLD guidelines[41], with the addition of a baseline VCTE (baseline liver function test + ultrasonography + VCTE). Sonography is key to detect early signs of portal hypertension e.g., splenomegaly +/- intra-abdominal varices, prompting the need for more definitive evaluation. Current therapeutic targets for pediatric MASLD would be weight loss and normalization of ALT, although future targets could include reduction in CAP/Liver stiffness indices in VCTE. There are no formal recommendations for the optimal follow-up intervals for VCTE monitoring to date.

Figure 1 Proposed algorithm for diagnosis and management of pediatric metabolic dysfunction-associated steatotic liver disease legend. ALT: Alanine aminotransferase; BMI: Body mass index; MASLD: Metabolic dysfunction-associated steatotic liver disease; HDL: High density lipoprotein; A1AT: Alpha 1 antitrypsin; DILI: Drug induced liver injury; IEM: Inborn error of metabolism; LFT: Liver function test; VCTE: Vibration-controlled transient elastography; CAP: Controlled attenuation parameter.

INTERVENTIONS FOR PEDIATRIC MASLD

Longitudinal follow-up data from clinical trials have demonstrated that one-third of children with steatosis go on to develop definite MASH with or without advanced fibrosis within 2 years[50]. In fact, a 10-year follow-up study of 51 adolescents had reported fibrosis progression in 16% of the cohort, where 6% developed advanced fibrosis[51]. While cirrhosis and MASLD-associated end stage liver disease are reportedly rare in the pediatric population, these late complications have been described[52,53]. These findings highlight the need for early detection and treatment of MASLD, especially in the pediatric age group.

Non-pharmacological interventions

Lifestyle interventions incorporating dietary modification and exercise to achieve weight loss have been the mainstay of management for pediatric MASLD[54]. Previous studies have suggested that weight loss as low as 1 kg can improve serum biomarkers of MASLD in children, and may also improve biopsy-proven MASLD when sustained weight loss is maintained for 24 months[55,56]. A BMI-z score reduction of 0.25 has been shown to be associated with significant improvements in serum ALT levels in children[57]. Lifestyle modifications focusing on diet and physical activity remain the first line treatment for MASLD in children. The lifestyle interventions that lead to improvements in BMI and waist circumference have been shown to improve MASH in children[50]. In recent clinical practice guidelines, intensive multi-component programs with high contact time have been recommended for management of obesity in children and adolescents[58,59]. These should readily incorporate changes that target behavior, motivation, dietary modifications and increased levels of physical activity. Importantly, the interventions should be available from multiple avenues, including in the community and schools where children spend the most time. Involving the family unit for weight interventions in children has been associated with higher success of weight loss compared to interventions that target the child alone[60]. Despite the importance of lifestyle modifications in managing pediatric MASLD, weight loss through lifestyle alone requires a high level of commitment and intrinsic motivation, which makes it challenging to sustain, especially in adolescents. Recently, there have been increasing use of adjunct pharmacological therapies for weight management in adolescents, which may also confer benefits to the clinical course of MASLD.

Early initiation of pharmacological interventions

Revisiting use of metformin for pediatric MASLD management: Metformin has been established as the first line treatment for T2DM in both adults and adolescents. It has been shown to improve insulin sensitivity and also confer modest benefit in terms of weight loss. As insulin resistance is a major contributor to the pathophysiology of MASLD, it is reasonable to postulate that metformin may lead to improvements in hepatic steatosis, even in children[61]. However, a systematic review and meta-analysis of 4 randomized controlled trials on the use of metformin in pediatric MASLD showed no significant improvement in liver enzymes. There was also insufficient pooled data to draw conclusions about the impact of metformin on liver ultrasonography or histology in pediatric patients with MASLD[62]. While use of metformin may indeed be helpful to some extent in children or adolescents with MASLD, there is no strong evidence currently to show that it reverses steatosis or reduces progression to fibrosis as a stand-alone agent. As such, metformin in itself may not be suitable as an early agent to halt the disease progression in pediatric MASLD. However, it can be considered in a subgroup of patients with glucose intolerance or established T2DM to drive improvement in insulin resistance and adiposity.

The promise of GLP-1RA in pediatric MASLD: GLP-1RA are incretin mimetics with excellent efficacy and safety profile in their use for obesity and diabetes mellitus, including in children and adolescents[63,64]. In addition to improvement in BMI and glycemic control, studies done in adults have also shown to offer multiple collateral benefits on metabolic health, such as dyslipidemia, polycystic ovarian syndrome and even MASLD[65-68]. Specifically, in the context of MASLD in adults, GLP-1RAs have been shown to improve hepatic insulin resistance, reduce free fatty acids, decrease intrahepatic triglycerides, which leads to reduced hepatic lipotoxicity[69,70]. The same may hold true for the adolescent population. For example, at present, liraglutide (Saxenda^®) and semaglutide (Wegovy^®) are approved by the Food and Drug Administration (FDA) for treatment of obesity in children aged 12 years and above. While increasing numbers of adolescents with obesity are using GLP-1RA for weight management, data on efficacy for pediatric MASLD have been limited, with minimal direct studies evaluating this. In the hallmark clinical trial of use of liraglutide for adolescents with obesity, trial end points did not include biomarkers of MASLD as an outcome[63]. For the once weekly semaglutide trial for adolescents with obesity, there was significant improvement in percentage change in alanine transaminase level of -14.1 [95% confidence interval (95%CI): -25.2 to -1.4] with semaglutide compared to placebo, after a mean difference in percentage change in BMI of -16.7 (95%CI: -20.3 to -13.2)[71]. A recent single center retrospective study had showed that 42 patients below age 18 years with MASLD who were treated with either liraglutide or semaglutide had significant reductions in ALT over 6 months, with greater improvements in those with underlying diabetes[72]. With the current evidence, a recent international consensus statement for pediatric MASLD has indeed recommended the use of GLP-1RA as part of the management for pediatric MASLD[7].

Earlier clinical trials on adult MASLD summarized in a systematic review meta-analysis in 2021 had reported that while GLP-1RA led to reduced steatosis in individuals with steatohepatitis, there were no statistically significant improvements in liver fibrosis[73]. The anti-fibrotic effects of liraglutide remain modest[54,74]. The outcome of the ESSENCE trial investigating subcutaneous semaglutide 2.4 mg for treatment of biopsy-proven MASH with fibrosis is currently pending[75]. However, the preliminary results of the trial appear promising, showing significant improvements in both steatohepatitis and fibrosis[76]. It showed resolution of steatohepatitis with no worsening of fibrosis in 62.9% vs 34.3% with placebo. Semaglutide also produced approximately 10% mean weight loss and broad improvements in non-invasive fibrosis/steatosis measures and cardiometabolic risk factors, with a gastrointestinal-tolerability-dominant safety profile and no new safety signals. This may lead to the eventual use of semaglutide specific for MASH, beyond just obesity and T2DM.

However, these outcomes have been not been replicated in the pediatric setting. To date, there has been no major studies evaluating the efficacy of GLP-1RA on pediatric MASLD using change in liver histology as an outcome. Despite that, as the beneficial effects of weight loss on pediatric MASLD have been well established, the potential impact of GLP-1RA in pediatric MASLD remains promising, with the hope that this will arrest further progression from steatosis to fibrosis if used timely at a younger age. Indeed, the recently published SCALE Kids trial on the use of liraglutide in children aged 6-12 years showing significant improvements in BMI compared to placebo with lifestyle interventions may lead to earlier initiation of GLP-1RA in pre-adolescents with obesity[77]. The hope is that earlier initiation of anti-obesity management can arrest the clinical progression of MASLD in the early stages, reducing the risk of liver fibrosis. Moving forward, future trials on GLP-1RA in children and adolescents should include an emphasis on outcomes specific to MASLD, including biochemical markers of hepatitis, and also on reversing steatosis and delaying progression to fibrosis.

Pushing boundaries - resmetirom for pediatric MASLD: Despite advancements in the understanding of the pathogenesis and clinical course of MASLD, the management of MASLD in both adults and adolescents have largely centered around weight management and improving insulin sensitivity. While these continue to be important aspects of the multi-faceted therapeutic care for individuals with MASLD, a horizon of new therapies has been emerging, including use of combination therapies for treatment of MASH and fibrosis[78].

Resmetirom, a successful example of the ongoing efforts in MASLD therapeutics, has recently received FDA approval for treatment of MASH in adults. This is in fact the first medication specifically indicated for treatment of MASH and fibrosis, and has been shown to be safe and effective in adults[79]. Resmetirom is an oral, liver-directed thyroid hormone receptor beta (THR-β) agonist. It selectively binds to THR-β that is predominantly expressed in the liver, mimicking the action of endogenous thyroid hormones, leading to fatty acid oxidation, reduction in intrahepatic lipogenesis and lipo-toxicity[80]. It also promotes increased mitochondrial biogenesis to improve capacity of handling the increased free fatty acids. These mechanisms in combination lead to reduction in hepatic steatosis, inflammation and fibrosis; the high hepatic THR-β selectively limits its effects on other thyroid hormone receptors found in the heart or bones, thereby reducing adverse systemic effects[80].

To date, there are no reports on the use of resmetirom in children or adolescents with MASH. The effects of this novel pharmacological intervention in children remains to be seen. Based on our current understanding of the clinical progression of MASLD across different age groups, as well as the mechanisms of action of resmetirom, there is reasonable hope that resmetirom may also show potential efficacy in treating pediatric MASH. While its safety profile in adults has been established, the studies are yet to be conducted in children to show that this is well tolerated in children, with minimal risk of significant adverse effects. One of the concerns regarding potential disruption of thyroid homeostasis in growing individuals is worthy of evaluation while doing trials in children; although the effects of resmetirom on thyroid homeostasis is minimal, since it has not been shown to impact thyroid function or activity outside of the liver[81]. The summary of studies on pharmacotherapy for pediatric MASLD is provided in Table 2[62,72,82].

Table 2 Summary of studies on pharmacotherapy for pediatric metabolic dysfunction-associated steatotic liver disease.

Medication class	Study design & population	Primary endpoint	Efficacy summary	Safety/adverse events	Ref.
GLP-1RA (liraglutide, semaglutide)	Retrospective cohort, n = 42, age ≤ 18 years, MASLD diagnosis, GLP-1RA prescribed for obesity or T2DM[1]	ALT reduction at 6 months and end-of-treatment	Significant mean ALT reduction (-56 U/L at 6 months, -37 U/L at EOT, P < 0.05); greater effect in T2DM; improvements in AST, GGT, HbA1c, triglycerides; BMI stabilization, not reduction	Mild-moderate GI symptoms (nausea, vomiting, diarrhea); no serious adverse events reported	Tou and Panganiban[72], 2025
Metformin	Meta-analysis	ALT reduction	No significant improvement in ALT	GI upset, rare lactic acidosis	Gkiourtzis et al[62], 2023
Lifestyle/standard of care	Longitudinal cohort, n = 440, pediatric MASLD	Composite improvement (ALT, GGT, histology)	22% improved at 1 year, 31% at 2 years; 20% worsened; BMI and cholesterol changes most associated with outcomes	Not applicable	Newton et al[82], 2025
Resmetirom	No pediatric studies to date

GLP-1RA: Glucagon-like peptide 1 receptor agonists; T2DM: Type 2 diabetes mellitus; ALT: Alanine aminotransferase; GGT: Gamma glutamyl transferase; HbA1c: Glycated hemoglobin; BMI: Body mass index; GI: Gastrointestinal; MASLD: Metabolic dysfunction-associated steatotic liver disease.

Gut microbiome manipulation strategies

Pediatric data on probiotic use in MASLD has been promising, with a recent meta-analysis of 657 participants demonstrating probiotics significantly reduce transaminases (ALT/AST) and lower triglyceride levels in both the adult and pediatric subgroups[83]. While the authors caution that these results were based on a small sample size of 69 children from three pediatric trials and there remains uncertainty which probiotic strain would be of greatest benefit, the data nevertheless suggests the potential of gut microbiome manipulation in the therapeutic management of obesity/MASLD. Fecal microbiota transplantation has likewise shown benefits in body composition and metabolic health outcomes in obese adolescents[84], reaffirming the role of the gut microbiome in obesity.

CURRENT LIMITATIONS AND FUTURE DIRECTIONS

Despite the improvements in recognition, diagnostics and treatment options for MASLD, there continues to be several limitations specific to the pediatric population. As alluded to above, most of the scientific data have been derived from adult studies, with limited studies in children guiding recommendations. Moreover, many of the studies presented come from high- or middle-income countries, whose data may be specific to populations of similar affluence, with more access to novel diagnostic tools and therapeutics for MASLD. This is an important limitation when considering the global application of the findings of this review.

As in many other areas of pharmacological development, clinical trials involving adolescent and pediatric populations often lag significantly behind those conducted in adults. In most instances, drugs are used extensively in adult populations long before formal pediatric trials are initiated. This is not surprising, as conducting trials in children can be particularly challenging. Multiple factors contribute to this, including the stricter ethical requirements surrounding children as a vulnerable population, consent and assent requirements, regulatory challenges and also acceptability to participants and caregivers, especially when outcome measures involve invasive procedures such as liver biopsy for histological assessment[85,86]. Even after trials are completed successfully, regulatory approval for pediatric use typically requires a longer timeline. Collectively, these barriers continue to hinder the timely introduction of novel therapies for pediatric MASLD.

Lastly, the exact nature of ‘improvement in pediatric MASLD’ is still poorly defined in existing literature, and treatment targets are likely to evolve with the utilization of more precise diagnostics of MASLD. A common therapeutic goal for MASLD is the normalization of transaminases, but future targets may include regression of hepatic steatosis and possibly stabilization or regression of hepatic fibrosis on non-invasive diagnostics.

As we look into the future for diagnostics and therapeutics for pediatric MASLD, key research priorities include well-designed randomized controlled trials evaluating GLP-1RA and other emerging therapeutics, as current evidence is largely extrapolated from adult studies. There is also a critical need to validate non-invasive diagnostic cut-offs - such as biomarkers, elastography thresholds, and risk-stratification tools - specifically for children. Finally, large longitudinal cohorts are essential to clarify the natural history of pediatric MASLD, identify early predictors of progression, and inform timing of intervention.

CONCLUSION

Pediatric MASLD has emerged as the most common cause for pediatric chronic liver disease in most regions worldwide, contemporaneous with the burgeoning pediatric obesity pandemic. There is an alarmingly high rate of children with obesity complicated by MASLD already presenting with advanced fibrosis, raising the necessity for accurate non-invasive diagnostics. These would allow further risk stratification of affected children to identify those at highest risk of disease progression who may benefit from aggressive weight control therapy. The advent of GLP-1RAs may add value to the overall management of pediatric obesity and MASLD, with potential hopes that early utilization of GLP-1RAs may retard disease progression and even support reversal of fibrosis. Novel anti-fibrotic agents such as resmetirom may have a role in the pediatric population in future, but barriers exist in the implementation of trials and testing in this age group. It is important that the clinical and scientific community recognize these barriers and make a concerted effort to tailor safe and ethical trials for pediatric patients, without extrapolation from adult studies or time delay.

ACKNOWLEDGEMENTS

We thank Dr. Dimple Rajgor for her assistance in editing, formatting, reviewing, and in submitting the manuscript for publication.