Residency · Residency · Medicine Pediatrics

Nonalcoholic Fatty Liver Disease in Children and Adults

Overview

Nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), is the most common chronic liver disease in both children and adults worldwide. Pediatric NAFLD has a distinct histologic pattern (zone 1 predominance) and is strongly linked to the obesity epidemic. The Med-Peds physician must understand screening, noninvasive assessment, and the emerging therapeutic landscape across ages.

Nomenclature Update (2023)

NAFLD has been renamed MASLD (metabolic dysfunction-associated steatotic liver disease) per multi-society consensus (AASLD/EASL) NASH has been renamed MASH (metabolic dysfunction-associated steatohepatitis) The new nomenclature requires the presence of at least one cardiometabolic risk factor (obesity, T2DM, dyslipidemia, HTN) alongside hepatic steatosis. For simplicity and familiarity, both terms are used in this review; clinical transition to MASLD/MASH terminology is ongoing.

Epidemiology

Pediatric NAFLD prevalence: 7-10% of all children; up to 34% of obese children. Adult NAFLD prevalence: 25-30% of the general population; up to 75-90% of morbidly obese adults. NAFLD is now the fastest-growing indication for liver transplantation in adults. Racial/ethnic disparities: highest prevalence in Hispanic populations, lowest in Black populations (in both children and adults) Male predominance in both age groups.

Pathophysiology

The "Multiple Hit" Model

First hit: hepatic steatosis driven by insulin resistance, increased free fatty acid flux from adipose tissue, and de novo lipogenesis. Additional hits: oxidative stress, mitochondrial dysfunction, lipotoxicity, gut microbiome alterations, genetic susceptibility (PNPLA3 I148M variant most significant) Progression: steatosis (benign) --> steatohepatitis (MASH, with inflammation and ballooning) --> fibrosis --> cirrhosis --> hepatocellular carcinoma.

Pediatric-Specific Features

Zone 1 (periportal) predominance: pediatric MASH characteristically shows inflammation and fibrosis in zone 1, versus zone 3 (pericentral/perivenular) pattern in adult MASH. Type 1 NASH (adult pattern): zone 3 steatosis, ballooning, and pericellular fibrosis. Type 2 NASH (pediatric pattern): zone 1 steatosis, portal inflammation, and portal fibrosis; may have NO ballooning. Some children show overlap (both patterns); the pediatric pattern may represent a distinct disease mechanism. Fibrosis may progress more rapidly than previously thought in children.

Risk Factors

Obesity: strongest risk factor in both populations; central adiposity (waist circumference) more predictive than BMI. Insulin resistance / Type 2 diabetes: central to NAFLD pathogenesis. Dyslipidemia: elevated triglycerides, low HDL. Genetics: PNPLA3 I148M (most significant), TM6SF2, HSD17B13 (protective), MBOAT7. Diet: high fructose, high saturated fat, ultra-processed foods. Sedentary lifestyle. Polycystic ovary syndrome: in adolescent and adult females. Obstructive sleep apnea: intermittent hypoxia promotes steatohepatitis. Medications: valproic acid, amiodarone, tamoxifen, corticosteroids, methotrexate.

Screening

Who to Screen

Children: NASPGHAN recommends screening obese children and overweight children with additional risk factors (central adiposity, insulin resistance, prediabetes/T2DM, dyslipidemia, family history of NAFLD/NASH, OSA) starting at age 9-11. Adults: AASLD recommends screening in patients with obesity, T2DM, or metabolic syndrome; universal screening of general population NOT yet recommended.

Screening Methods

ALT: most accessible but imperfect; upper limit of normal for pediatrics: 22 U/L (girls), 26 U/L (boys) per NASPGHAN. Normal ALT does NOT exclude NAFLD -- up to 50% of patients with NAFLD have normal ALT. Ultrasound: detects steatosis (echogenic liver); sensitivity decreases when steatosis <30%; cannot reliably detect fibrosis or inflammation. Controlled attenuation parameter (CAP) on FibroScan: quantifies steatosis non-invasively.

Diagnosis

Noninvasive Assessment

Biomarkers for Fibrosis

FIB-4 Index: age, AST, ALT, platelet count; validated in adults; low cutoff <1.3 (low risk), high cutoff >2.67 (high risk); less validated in pediatrics. NAFLD Fibrosis Score (NFS): age, BMI, diabetes status, AST/ALT ratio, platelets, albumin; adults. AST-to-platelet ratio index (APRI): simple calculation; modest accuracy for fibrosis. Pediatric: no well-validated non-invasive fibrosis score; enhanced liver fibrosis (ELF) test and FibroScan are being studied.

Imaging for Fibrosis

Transient elastography (FibroScan): measures liver stiffness as surrogate for fibrosis; available for adults and children (pediatric probes available); cutoffs differ by BMI and etiology. MR elastography (MRE): most accurate noninvasive measure of fibrosis; expensive, limited availability. MRI-PDFF (proton density fat fraction): gold standard for quantifying hepatic steatosis; useful for research and clinical trials.

Liver Biopsy

Remains the gold standard for diagnosis and staging of MASH/fibrosis. Indications: diagnostic uncertainty (exclude other liver diseases), assess severity/stage when noninvasive tests are indeterminate, suspected advanced fibrosis, clinical trials. NAS (NAFLD Activity Score): steatosis (0-3) + lobular inflammation (0-3) + ballooning (0-2); NAS >=5 correlates with MASH. Fibrosis staging: F0 (none) to F4 (cirrhosis) Pediatric-specific: may show zone 1 pattern not captured by standard NAS scoring.

Differential Diagnosis

Exclude other causes of elevated ALT/steatosis: alcohol use, viral hepatitis (B, C), autoimmune hepatitis, Wilson disease (check ceruloplasmin in children/young adults), alpha-1 antitrypsin deficiency, celiac disease, thyroid disease, drug-induced liver injury.

Management

Lifestyle Modification (First-Line for All)

Weight loss: 5-7% body weight loss improves steatosis; 7-10% may improve MASH and fibrosis. Diet: Mediterranean diet (adults, strongest evidence); reduce sugar-sweetened beverages and fructose; increase fiber, fruits, vegetables, whole grains; reduce ultra-processed foods. Exercise: 150-300 minutes/week moderate-intensity aerobic exercise in adults; 60 minutes/day in children; exercise improves hepatic steatosis independent of weight loss. Behavioral counseling: motivational interviewing, family-based approaches in children.

Pharmacotherapy

Adults with MASH

Pioglitazone: improves MASH histology (reduces steatosis, inflammation, and ballooning); NOT approved specifically for MASH; side effects include weight gain, fluid retention, fracture risk, bladder cancer concern. Vitamin E (800 IU/day): PIVENS trial showed improvement in MASH histology in non-diabetic adults; concerns about long-term safety (increased prostate cancer, hemorrhagic stroke in some studies) Resmetirom (Rezdiffra): thyroid hormone receptor beta agonist; FDA-approved (2024) for non-cirrhotic MASH with moderate-to-advanced fibrosis (F2-F3); first FDA-approved drug for MASH. GLP-1 receptor agonists (semaglutide, liraglutide): significant reduction in MASH and steatosis; semaglutide improved MASH resolution in SURGE trial; not yet FDA-approved specifically for MASH but widely used in patients with co-existing T2DM/obesity. SGLT2 inhibitors: modest benefit on hepatic steatosis; being studied in MASH trials.

Pediatric MASH

NO FDA-approved pharmacotherapy for pediatric NAFLD/MASH. Vitamin E: TONIC trial (pediatric) showed improvement in MASH histology with vitamin E 800 IU/day vs. placebo and metformin; vitamin E is the most commonly used pharmacotherapy for pediatric MASH. Metformin: TONIC trial showed NO benefit for pediatric MASH; NOT recommended. GLP-1 agonists: pediatric trials ongoing; semaglutide approved for adolescent obesity (age >=12) and may benefit NAFLD indirectly. Lifestyle modification remains the cornerstone of pediatric management.

Bariatric/Metabolic Surgery

Adults: RYGB and sleeve gastrectomy significantly improve NAFLD/MASH, including resolution of MASH and regression of fibrosis in many patients. Adolescents: limited data but increasingly considered for severe obesity with NAFLD as a comorbidity; FDA-approved devices and procedures available for ages >=12 in some centers.

Liver Transplantation

For decompensated cirrhosis or hepatocellular carcinoma. NAFLD/MASLD is now the most rapidly growing indication for liver transplant in adults. Risk of NAFLD recurrence in transplanted liver (due to persistent metabolic risk factors) Rare in pediatrics but may be needed for end-stage NAFLD-related cirrhosis.

Long-Term Complications and Surveillance

Hepatocellular carcinoma (HCC): can develop even without cirrhosis in NAFLD (unique compared to other liver diseases); surveillance with ultrasound +/- AFP every 6 months in cirrhotic patients. Cardiovascular disease: leading cause of mortality in NAFLD patients (NOT liver disease); aggressive cardiovascular risk factor management is essential. Type 2 diabetes: NAFLD increases T2DM risk 2-5x; screen regularly. CKD: NAFLD associated with increased CKD risk. Colorectal neoplasia: increased risk of adenomatous polyps; ensure age-appropriate CRC screening.

<image>A histologic comparison showing the two patterns of NASH across ages. The left panel shows the adult (Type 1) pattern with zone 3 pericentral steatosis, hepatocyte ballooning, and pericellular fibrosis illustrated on a liver lobule diagram. The right panel shows the pediatric (Type 2) pattern with zone 1 periportal steatosis, portal inflammation, and portal fibrosis on the same liver lobule schematic. Color coding distinguishes the zones, with annotation explaining that these distinct histologic patterns may reflect different disease mechanisms and have implications for noninvasive assessment tools validated primarily on the adult pattern.</image>

<image>A screening and diagnostic algorithm for NAFLD/MASLD in children and adults. The pediatric pathway starts with screening ALT in obese or at-risk children ages 9-11, using sex-specific upper limits (22 U/L girls, 26 U/L boys), proceeding to ultrasound and exclusion of secondary causes, then FibroScan or liver biopsy for staging. The adult pathway starts with identification of metabolic risk factors, ALT, FIB-4 index for fibrosis risk stratification, then FibroScan or MRE for intermediate-risk patients, and liver biopsy for indeterminate cases. Both pathways converge on management decisions based on MASH presence and fibrosis stage.</image>

<image>A treatment landscape infographic for NAFLD/MASLD showing available and emerging therapies. A central pyramid has lifestyle modification (diet, exercise, weight loss) as the broad base for all patients. The second tier shows currently available pharmacotherapy: vitamin E (pediatric and adult), pioglitazone (adult), resmetirom (adult, FDA-approved 2024), and GLP-1 agonists (adult, off-label for MASH). The third tier shows bariatric surgery for severe obesity. The apex shows liver transplantation for end-stage disease. A sidebar shows the pediatric treatment gap with "NO FDA-approved therapy" highlighted and vitamin E as the only pharmacotherapy with pediatric trial support.</image>

Clinical Pearls

NAFLD is the most common liver disease in children and adults -- it should be on the differential for any child or adult with elevated transaminases. Use sex-specific ALT upper limits in children (22 U/L girls, 26 U/L boys) -- "normal" lab reference ranges are too high and miss early NAFLD. Normal ALT does NOT exclude NAFLD -- up to 50% of patients with steatosis have normal transaminases. Pediatric MASH has a distinct zone 1 (periportal) histologic pattern, unlike the zone 3 pattern in adults -- this has implications for noninvasive assessment tools. Cardiovascular disease, NOT liver disease, is the leading cause of death in NAFLD patients -- aggressive management of metabolic risk factors is essential. Resmetirom (2024) is the first FDA-approved drug for MASH with fibrosis in adults -- a landmark in NAFLD therapeutics. Metformin does NOT improve MASH (TONIC trial) and should not be used specifically for this indication. Weight loss of 7-10% can improve MASH histology and even reverse fibrosis -- lifestyle modification remains the most important intervention across all ages. Screen for NAFLD in all obese children starting at age 9-11 per NASPGHAN guidelines.

References

• Vos MB, Abrams SH, Barlow SE, et al. NASPGHAN clinical practice guideline for the diagnosis and treatment of nonalcoholic fatty liver disease in children. J Pediatr Gastroenterol Nutr. 2017;64(2):319-334.
• Rinella ME, Lazarus JV, Ratziu V, et al. A multi-society Delphi consensus statement on new fatty liver disease nomenclature (MASLD). Hepatology. 2023;78(6):1966-1986.
• Lavine JE, Schwimmer JB, Van Natta ML, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents (TONIC trial). JAMA. 2011;305(16):1659-1668.
• Harrison SA, Bedossa P, Guy CD, et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med. 2024;390(6):497-509.
• Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis (PIVENS trial). N Engl J Med. 2010;362(18):1675-1685.

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