What are the causes of hepatic steatosis?

Causes of Hepatic Steatosis

Hepatic steatosis (fatty liver) has multiple etiologies that can be categorized into metabolic, alcohol-related, medication-induced, and other specific causes. 1

Primary Causes

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

• Previously known as Non-Alcoholic Fatty Liver Disease (NAFLD) 2
• Most common cause in developed countries (20-30% prevalence) 2
• Associated with:
  • Obesity
  • Type 2 diabetes mellitus
  • Insulin resistance
  • Metabolic syndrome
  • Dyslipidemia
  • Hypertension 1, 2

Alcohol-Related Liver Disease

• Significant alcohol consumption (>14 drinks/week for women, >21 drinks/week for men) 1
• Mechanisms include:
  • Increased NADH synthesis
  • Increased triglyceride and fatty acid synthesis
  • Suppression of mitochondrial β-oxidation
  • Increased free fatty acid influx from adipose tissue
  • Acetaldehyde-induced mitochondrial damage 1

Medication-Induced Hepatic Steatosis

Macrovesicular Steatosis-Inducing Medications

• Amiodarone
• Methotrexate
• Tamoxifen
• Corticosteroids
• NSAIDs 1, 3

Microvesicular Steatosis-Inducing Medications

• Valproic acid
• Anti-retroviral medications
• Tetracyclines 1

Other Specific Causes

Viral Infections

• Hepatitis C (particularly genotype 3) 1

Nutritional and Metabolic Disorders

• Starvation
• Rapid weight loss
• Parenteral nutrition
• Abetalipoproteinemia
• Wilson's disease
• Lipodystrophy 1

Endocrine Disorders

• Hypothyroidism
• Hypopituitarism
• Hypogonadism
• Polycystic ovary syndrome 1

Genetic Disorders

• Lysosomal acid lipase deficiency (LAL-D)
• Familial hypobetalipoproteinemia
• Cholesterol ester storage disease
• Wolman disease
• PNPLA3, TM6SF2, MBOAT7, GCKR genetic variants 1

Pregnancy-Related

• Acute fatty liver of pregnancy
• HELLP syndrome 1

Other Causes

• Sleep apnea
• Toxin exposures (e.g., vinyl chloride)
• Reye's syndrome 1

Pathophysiological Mechanisms

The development of hepatic steatosis involves several mechanisms:

1. Increased lipogenesis: Enhanced synthesis of fatty acids and triglycerides in hepatocytes 1
2. Decreased fatty acid secretion: Impaired export of lipids from the liver 3
3. Mitochondrial dysfunction: Interruption of β-oxidation of fatty acids 4, 5
4. Oxidative stress: Production of reactive oxygen species leading to lipid peroxidation 4
5. Inflammatory response: Cytokine activation and inflammatory cell infiltration 1

Clinical Approach to Diagnosis

When evaluating a patient with suspected hepatic steatosis:

1. Assess alcohol consumption: Document detailed alcohol history using standardized tools like AUDIT-C 1
2. Review medications: Identify potentially steatogenic drugs 1
3. Evaluate metabolic risk factors: Screen for obesity, diabetes, dyslipidemia, and hypertension 1
4. Exclude other liver diseases: Perform comprehensive serological testing (viral hepatitis, autoimmune markers, iron studies, ceruloplasmin) 1
5. Consider genetic testing: In lean individuals with steatosis or those with family history of liver disease 1

Imaging and Diagnosis

• Ultrasound is the first-line investigation (84.8% sensitivity and 93.6% specificity for moderate-severe steatosis) 1, 2
• Advanced imaging techniques like elastography and MRI can provide more accurate quantification of fat content and assess fibrosis 2
• Liver biopsy remains the gold standard for definitive diagnosis and staging 2

Important Clinical Considerations

• Hepatic steatosis is often asymptomatic until advanced stages 6
• The presence and progression of liver fibrosis is the main predictor of liver-related mortality 7
• Early recognition of drug-induced steatohepatitis is crucial as some forms may progress even after discontinuation of the causative agent 5
• Regular monitoring is recommended for patients with risk factors, with follow-up intervals of 1-3 years depending on fibrosis risk 2