Treatment response in pediatric metabolic dysfunction-associated steatotic liver disease: Noninvasive endpoints and body composition

Table 1 Candidate response endpoints in pediatric metabolic dysfunction-associated steatotic liver disease: Validation, responsiveness, feasibility, and limitations

Domain/measure	Primary use	Pediatric validation/evidence source	Longitudinal responsiveness	Feasibility/cost	Major confounders and limitations	Pragmatic reassessment interval	Evidence certainty for response
Biochemical injury: ALT, AST, GGT	Serial injury signal; treatment trend	Sex-specific ALT reference limits; dynamic ALT/GGT associated with paired histological change[18,19,38,39]	Responsive over weeks to months, but incomplete surrogate for MASH or fibrosis	High feasibility; low cost	Laboratory method, biological variation, exercise, illness, medications, other liver disease; normal ALT does not exclude MASH/fibrosis	8-12 weeks after major treatment change, then every 3-6 months during active care	Moderate for longitudinal biochemical change; low for stand-alone histological response
Steatosis: MRI-PDFF	Quantitative liver fat	Strong pediatric diagnostic accuracy; limited paired-biopsy response data[28,41,42]	Responsive to liver-fat change; pediatric meaningful-change threshold not validated	Limited availability; high cost; no ionizing radiation	Scanner/protocol differences, precision limits, motion; steatosis change does not prove MASH/fibrosis response	Approximately 6-12 months when clinically actionable	Moderate for steatosis change; low for pediatric histological surrogate
Fibrosis risk: MRE	Cross-sectional stiffness/fibrosis risk	Good pediatric diagnostic performance for advanced fibrosis[47,48]	Short-term responsiveness uncertain; no pediatric minimum important change	Tertiary-center availability; high cost	Inflammation, congestion, cholestasis, fasting, scanner/protocol, motion; fibrosis changes slowly	Approximately 12-24 months in stable care; earlier if high risk	Moderate for cross-sectional fibrosis; low for treatment response
Fibrosis/steatosis: VCTE and CAP	Point-of-care stiffness and attenuation	Pediatric cross-sectional studies and emerging longitudinal cohorts[49,50,54,55]	Potentially responsive, but validated pediatric thresholds absent	Moderate cost; portable; rapid	Fasting, probe selection, severe obesity, technical failure, operator/device, inflammation; CAP variability	Approximately 12-24 months, standardized to same device/probe	Low-to-moderate; emerging longitudinal evidence
Histology: MASH diagnosis, NAS components, fibrosis stage	Reference standard for activity and fibrosis; trial anchor	Pediatric portal-predominant patterns and validated scoring systems[35,36]	Can demonstrate response over 1-2 years but sampling and reader variability affect change	Invasive; high burden and cost	Sampling error, interobserver variation, attrition, ethics; NAS is not a diagnostic threshold	Only when clinically or scientifically justified	High as reference standard; feasibility limits routine use
Serum fibrosis/injury biomarkers: ELF, PRO-C3, cytokeratin-18	Fibrosis or cell-death biology; adjunctive risk assessment	ELF and PRO-C3 have pediatric histology associations[61,62]	Longitudinal response data limited; assay-specific thresholds not established	Variable availability and cost	Assay platform, specimen handling, age, puberty, growth, analytical variation	Research protocol or selected specialist use	Low for routine response assessment
Composite panels: PNFI, PNFS, Fibro-PeN, pFIB	Cross-sectional fibrosis classification/triage	Pediatric derivation or validation, with variable external performance[56-60]	Not validated to quantify treatment-induced change	High feasibility if routine variables available	Population spectrum, age, prevalence, calibration; classification is not responsiveness	Not recommended as sole serial endpoint	Low for longitudinal response
Adiposity: %BMIp95, BMI Z score, waist, fat mass	Growth-adjusted obesity response	Widely used pediatric measures; linked to liver and metabolic change[18,80]	Responsive; interpretation depends on growth and treatment modality	High feasibility; low cost; fat-mass methods add cost	Puberty, height growth, edema, body-size limitations of Z scores; adiposity is not liver response	Every clinical visit; formal summary every 3-6 months	Moderate as complementary domain
Muscle quantity and function: BIA, DXA, handgrip, D3-creatine	Lean tissue, muscle, and function	Associations with pediatric disease severity and validation against MRI; no accepted pediatric sarcopenia criteria[63-65,67,71]	Potentially responsive, but method-specific error and growth complicate change	BIA/handgrip low-moderate cost; DXA/D3-creatine higher cost/limited	Hydration, device equations, effort, maturation, body size; lean mass loss is not synonymous with sarcopenia	6-12 months after intensive weight-loss therapy when actionable	Low-to-moderate as complementary domain
Cardiometabolic, growth, safety, and patient-reported outcomes	Whole-patient benefit and harm	Validated component measures exist; no universal pediatric MASLD core set[1,77]	Responsive according to domain and treatment; essential for net clinical benefit	Most clinical measures feasible; patient-reported tools require workflow	Treatment burden, missing data, instrument selection, developmental stage, social context	Every visit for safety; 3-12 months by domain	Moderate as essential complementary outcomes

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transferase; MASH: Metabolic dysfunction-associated steatohepatitis; MRI-PDFF: Magnetic resonance imaging proton density fat fraction; MRE: Magnetic resonance elastography; VCTE: Vibration-controlled transient elastography; CAP: Controlled attenuation parameter; NAS: Nonalcoholic Fatty Liver Disease Activity Score; ELF: Enhanced liver fibrosis; PRO-C3: N-terminal pro-peptide of type III collagen; PNFI: Pediatric Nonalcoholic Fatty Liver Disease Fibrosis Index; PNFS: Pediatric Nonalcoholic Fatty Liver Disease Fibrosis Score; PeN: Fibrosis in Pediatrics with Nonalcoholic Fatty Liver Disease; pFIB: Pediatric Fibrosis Score; %BMIp95: Percentage of the 95^th percentile for body mass index; BMI: Body mass index; BIA: Bioelectrical impedance analysis; DXA: Dual-energy X-ray absorptiometry; D3-creatine: Deuterated-creatine dilution; MRI: Magnetic resonance imaging; MASLD: Metabolic dysfunction-associated steatotic liver disease.

Table 2 Three-tier, treatment-aware framework for response assessment in pediatric metabolic dysfunction-associated steatotic liver disease

Tier	Purpose and setting	Core domains	Suggested measures	Timing	Interpretation principles
Tier 1: Minimum clinical assessment	All care settings; establish direction, safety, and treatment exposure	Treatment/adherence; growth-adjusted adiposity; biochemical injury; cardiometabolic health; growth/puberty; safety; patient priorities	Treatment dose/exposure; height and growth velocity; %BMIp95 or BMI trajectory; ALT, AST, GGT; glucose/HbA1c, lipids, blood pressure; symptoms, quality of life, burden, physical function	Baseline; approximately 8-12 weeks after major change; then every 3-6 months during active treatment	Report achieved value, absolute change, relative change, and threshold crossing separately. Do not label normal ALT as histological remission. Evaluate alternative causes and access barriers
Tier 2: Specialist-center assessment	Clarify steatosis/fibrosis risk, discordance, or tissue consequences when results will change care	Quantitative steatosis; stiffness; standardized body composition and function; modality-specific safety	MRI-PDFF when available; MRE or standardized VCTE; BIA or DXA plus handgrip/functional assessment; nutrition and bone assessment after surgery	MRI-PDFF approximately 6-12 months after intensive intervention; elastography approximately 12-24 months in stable care; individualized sooner for high risk	Use the same scanner/device/probe and standardized fasting/quality criteria. Interpret liver fat, stiffness, adiposity, and muscle as separate axes. Adult thresholds are not automatically pediatric thresholds
Tier 3: Research endpoints	Trials and mechanistic cohorts; validate meaningful longitudinal change and core outcomes	Histology; advanced imaging; serum/molecular biomarkers; direct muscle measures; standardized patient-reported outcomes; feasibility and equity	Paired biopsy when ethically justified; centralized imaging; ELF, PRO-C3, cytokeratin-18 or omics; D3-creatine or detailed DXA; prespecified quality-of-life and treatment-burden instruments	Prespecified by biological timescale and intervention; generally 6-24 months with repeated exposure and safety measures	Anchor change to histology, function, clinical risk, or patient-important benefit; quantify measurement error and missingness; validate across puberty, treatment modalities, and diverse populations

BMI: Body mass index; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transferase; HbA1c: Glycated hemoglobin; MRI-PDFF: Magnetic resonance imaging proton density fat fraction; MRE: Magnetic resonance elastography; VCTE: Vibration-controlled transient elastography; BIA: Bioelectrical impedance analysis; DXA: Dual-energy X-ray absorptiometry; ELF: Enhanced liver fibrosis; PRO-C3: N-terminal pro-peptide of type III collagen; D3-creatine: Deuterated-creatine dilution.