What are the common causes of fatty liver disease in a pediatric patient?

Causes of Fatty Liver in Pediatric Patients

The most common cause of fatty liver in children is non-alcoholic fatty liver disease (NAFLD) driven by obesity and insulin resistance, but in very young or non-overweight children, you must immediately investigate for monogenic disorders including fatty acid oxidation defects, lysosomal storage diseases, and peroxisomal disorders. 1

Primary Metabolic Causes (Most Common)

Obesity-Related NAFLD

• Obesity is the dominant cause, present in 70-90% of pediatric fatty liver cases, with prevalence reaching 40-45% in obese adolescents 1, 2
• Insulin resistance and metabolic syndrome are the primary pathogenic mechanisms, with components including dyslipidemia, hypertension, and central adiposity collectively promoting hepatic steatosis 1, 2, 3
• Type 2 diabetes and prediabetes significantly increase NAFLD risk, with disease severity correlating with degree of metabolic dysfunction 3, 4
• Male gender, Hispanic ethnicity, and adolescent age (due to pubertal hormonal changes affecting insulin resistance) are independent risk factors 1, 5

Genetic Predisposition

• PNPLA3 gene polymorphism (rs738409) is strongly associated with hepatic steatosis in children, with the I148M variant conveying susceptibility to fatty liver 3
• Family history of severe NAFLD or cirrhosis increases risk, with first-degree relatives of affected children showing higher fat fractions than BMI-matched controls 1, 6

Monogenic and Metabolic Disorders (Critical to Exclude in Specific Populations)

These must be ruled out in children who are very young (<10 years) or not overweight with fatty liver: 1, 7

Fatty Acid and Carnitine Metabolism Defects

• Fatty acid oxidation defects present with hepatic steatosis and should be tested early in non-obese children 1, 7
• Carnitine metabolism disorders can manifest as fatty liver with hypoglycemia 1

Storage and Peroxisomal Disorders

• Lysosomal storage diseases (including lysosomal acid lipase deficiency) present with hepatic fat accumulation 1, 7
• Peroxisomal disorders (including Refsum disease) cause fatty liver through impaired lipid metabolism 1
• Glycogen storage diseases manifest with hepatomegaly, cirrhosis, and can progress to hepatocellular carcinoma 1, 7

Other Genetic Syndromes

• Wilson's disease presents with acute or chronic hepatitis, neurological dysfunction, and hemolytic anemia 7, 2
• Alpha-1-antitrypsin deficiency causes chronic liver disease with steatosis 1, 2
• Hereditary tyrosinemia type 1 typically presents in infants with systemic illness and liver dysfunction 1, 7
• Syndromic causes: Bardet-Biedl syndrome, Prader-Willi syndrome, Turner syndrome, Cohen syndrome 1
• Cystic fibrosis can present with fatty liver disease 1

Secondary Causes (Must Be Excluded)

Medication-Induced Steatosis

• Steatogenic medications including amiodarone, methotrexate, tamoxifen, and corticosteroids directly cause hepatic fat accumulation 2
• Drug hepatotoxicity should be ruled out through careful medication history, particularly when diagnosis is uncertain 1

Viral Hepatitis

• Hepatitis C genotype 3 directly causes hepatic steatosis independent of metabolic factors 2
• Viral hepatitis must be excluded before diagnosing NAFLD 3, 4

Autoimmune Liver Disease

• Low-titer autoantibodies are commonly present in pediatric NAFLD, but higher titers with elevated aminotransferases and high globulins warrant liver biopsy to exclude autoimmune hepatitis 1, 6, 7
• This distinction is critical as treatment differs fundamentally between NAFLD and autoimmune hepatitis 1

Diagnostic Algorithm by Clinical Presentation

Obese/Overweight Child (>85th percentile BMI)

• Primary consideration: NAFLD related to metabolic syndrome 1, 6
• Screen with ALT starting at age 10 years (or earlier with additional risk factors) 1, 6
• Evaluate for metabolic syndrome components: insulin resistance, dyslipidemia, hypertension 1, 2

Very Young Child (<10 years) or Non-Overweight Child

• Immediately test for monogenic disorders: fatty acid oxidation defects, lysosomal storage diseases, peroxisomal disorders 1, 6, 7
• Consider Wilson's disease, alpha-1-antitrypsin deficiency, glycogen storage diseases 1, 7
• Obtain detailed family history for genetic syndromes 1

Child with Elevated Autoantibodies

• If low titers: likely NAFLD with incidental autoantibodies 1
• If high titers with elevated aminotransferases and globulins: perform liver biopsy to exclude autoimmune hepatitis 1, 6, 7

Critical Pitfalls to Avoid

• Do not assume all fatty liver in obese children is benign NAFLD—progression to cirrhosis can occur, with cases reported as young as 8 years old 1
• Do not miss monogenic disorders in young or non-overweight children, as these require specific treatments fundamentally different from NAFLD management 1, 7
• Do not overlook medication history—steatogenic drugs are an important reversible cause 2
• Normal ALT does not exclude NAFLD, especially in morbidly obese children who should undergo ultrasound even with normal liver enzymes 6
• NAFLD is severely underdiagnosed in children due to lack of recognition and screening by healthcare providers 1, 6