What are the most common causes of hepatomegaly and steatosis?

Most Common Causes of Hepatomegaly and Steatosis

The most common causes of hepatomegaly and steatosis are metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD), alcohol-related liver disease, and medication-induced steatosis. 1, 2

Primary Causes

1. Metabolic Risk Factors (MASLD)

• Obesity (BMI >25 kg/m² or >23 kg/m² in Asian populations) 1
• Type 2 diabetes and insulin resistance 1
• Dyslipidemia (elevated triglycerides >1.7 mmol/L, low HDL) 1
• Hypertension (>130/85 mmHg) 1
• Metabolic syndrome 2

2. Alcohol Consumption

• Significant alcohol intake (>14 drinks/week for women, >21 drinks/week for men) 1, 2
• MetALD (combined metabolic and alcohol factors): 20-50 g/day for females and 30-60 g/day for males 1

3. Medication-Induced

• Common medications causing steatosis include: 2
  • Amiodarone
  • Methotrexate
  • Tamoxifen
  • Corticosteroids
  • NSAIDs

Other Important Causes

4. Viral Hepatitis

• Hepatitis C virus (particularly genotype 3) directly induces steatosis 1, 2, 3
• Chronic HBV can be associated with steatosis 3

5. Genetic/Inherited Conditions

• Hypobetalipoproteinemia 1
• Lysosomal acid lipase deficiency (Wolman disease, CESD) 1
• Wilson's disease 1
• Genetic variants (PNPLA3, TM6SF2, MBOAT7, GCKR) 2

6. Nutritional Factors

• Severe malnutrition 1
• Parenteral nutrition 1
• Rapid weight loss (post-bariatric surgery) 1

7. Endocrine Disorders

• Hypothyroidism 1
• Polycystic ovary syndrome (PCOS) 1
• Growth hormone deficiency 1
• Panhypopituitarism 1

8. Other Conditions

• HIV infection and antiretroviral therapy 4
• Pregnancy-related conditions (HELLP syndrome, acute fatty liver of pregnancy) 1
• Celiac disease 1

Classification of Steatosis

Macrovesicular Steatosis

• Large fat droplets in hepatocytes
• Associated with metabolic syndrome, alcohol, medications
• Severity classified as:
  • Mild: 10-30% of hepatocytes affected
  • Moderate: 30-60% of hepatocytes affected
  • Severe: >60% of hepatocytes affected 2

Microvesicular Steatosis

• Tiny lipid droplets (<1mm) giving foamy appearance to cytoplasm
• Associated with drug toxicity, acute fatty liver in pregnancy, Reye syndrome 2

Diagnostic Approach

When evaluating hepatomegaly and steatosis, a systematic approach should be followed:

1. Assess for metabolic risk factors (obesity, diabetes, dyslipidemia, hypertension) 1
2. Quantify alcohol consumption using standardized tools 1, 2
3. Review medication history for potentially steatogenic drugs 2
4. Exclude other liver diseases through comprehensive serological testing 1
5. Consider genetic testing in lean individuals with steatosis or those with family history 2

Clinical Pearls

• MASLD (formerly NAFLD) is now recognized as the hepatic manifestation of metabolic syndrome 5
• Hepatic steatosis can progress through inflammatory stages (steatohepatitis), fibrosis, cirrhosis, and even liver cancer 2
• The presence of both viral hepatitis and metabolic factors can accelerate liver disease progression 5, 3
• Steatosis can present in various patterns: diffuse, heterogeneous, focal, multinodular, perilesional, perivascular, subcapsular, and lobar forms 6
• Early recognition of drug-induced steatohepatitis is crucial, as some forms may progress even after discontinuation of the causative agent 2

Understanding the specific etiology of hepatic steatosis is essential for appropriate management and prevention of disease progression.