What are the primary causes and management options for fatty liver disease?

Causes of Fatty Liver Disease

Primary Causes

Fatty liver disease is fundamentally caused by metabolic dysfunction, with obesity, type 2 diabetes, and insulin resistance being the primary drivers, though secondary causes including medications, alcohol, and genetic conditions must be systematically excluded. 1

Metabolic Risk Factors (Most Common)

• Obesity: The strongest risk factor, present in the majority of NAFLD cases, with prevalence reaching 30-40% in the general US population 1
• Type 2 diabetes mellitus: Patients with diabetes have higher prevalence of NAFLD and more advanced disease including NASH and fibrosis 1
• Insulin resistance: Present even in lean individuals with NAFLD, driving hepatic fat accumulation independent of body weight 2
• Dyslipidemia: Part of the metabolic syndrome cluster that promotes hepatic steatosis 1
• Metabolic syndrome: The constellation of metabolic abnormalities that directly correlates with liver fat content 2

Demographic and Genetic Factors

• Age: NAFLD prevalence increases with age, and older patients face higher risk of progression to advanced fibrosis 1
• Male gender: Men have approximately twice the prevalence (31%) compared to women (16%) 1
• Ethnicity: Hispanic individuals have significantly higher prevalence, while non-Hispanic blacks have lower prevalence compared to non-Hispanic whites 1
• Genetic variants: PNPLA3 I148M, TM6SF2 E167K, and other variants increase susceptibility to steatosis, inflammation, fibrosis, and HCC risk 1

Endocrine Disorders

• Hypothyroidism: Independent risk factor for NAFLD even in non-obese individuals 1
• Hypopituitarism: Associated with increased NAFLD risk 1
• Hypogonadism: Contributes to hepatic steatosis independent of obesity 1
• Polycystic ovary syndrome (PCOS): Important risk factor independent of obesity 1

Secondary Causes (Must Be Excluded)

Macrovesicular Steatosis

• Excessive alcohol consumption: Defined as >21 standard drinks/week in men or >14 drinks/week in women over a 2-year period 1
• Hepatitis C (genotype 3): Directly causes hepatic steatosis 1
• Medications:
  • Amiodarone 1
  • Methotrexate 1
  • Tamoxifen 1
  • Corticosteroids 1
• Wilson's disease: Must be excluded in younger patients with unexplained steatosis 1
• Lipodystrophy: Including HIV-associated and non-HIV forms 1
• Nutritional causes: Starvation, parenteral nutrition 1
• Abetalipoproteinemia: Rare genetic disorder 1

Microvesicular Steatosis

• Medications: Valproate, anti-retroviral medicines 1
• Reye's syndrome 1
• Acute fatty liver of pregnancy 1
• HELLP syndrome 1
• Inborn errors of metabolism: LCAT deficiency, cholesterol ester storage disease, Wolman disease, lysosomal acid lipase deficiency (LAL-D) 1

Rare Genetic Causes in Lean NAFLD

• Familial hypobetalipoproteinemia 1
• Abetalipoproteinaemia 1

Diagnostic Approach to Identify Causes

Initial Evaluation

• Alcohol history: Use sensitive biomarkers (urine ethyl glucuronide, blood phosphatidylethanol) if under-reporting suspected 1
• Medication review: Identify all steatogenic medications 1
• Exclude competing liver diseases: Test for hemochromatosis (HFE gene if ferritin elevated), autoimmune hepatitis (though low-titer autoantibodies are common epiphenomena in NAFLD), chronic viral hepatitis, alpha-1 antitrypsin deficiency, Wilson's disease 1
• Assess metabolic risk factors: Screen for diabetes, measure lipid panel, calculate BMI, assess for metabolic syndrome components 1

Special Considerations for Lean NAFLD

• Visceral obesity assessment: Lean individuals may have excess visceral fat despite normal BMI 1
• Dietary patterns: High fructose or high fat intake can cause steatosis in lean individuals 1
• HIV testing: Consider in appropriate clinical context 1
• Endocrine evaluation: Test thyroid function, consider evaluation for other endocrine disorders if metabolic risk factors absent 1

Clinical Pitfalls

• Low-titer autoantibodies: Antinuclear antibodies >1:160 or anti-smooth muscle antibodies >1:40 occur in 21% of NAFLD patients and are generally clinically insignificant epiphenomena, not indicating autoimmune hepatitis 1
• Elevated ferritin: Common in NAFLD without indicating iron overload; only pursue hemochromatosis testing if transferrin saturation also elevated 1
• Normal liver enzymes: Do not exclude NAFLD or even NASH; liver biochemistries can be normal in patients with significant disease 1
• Alcohol threshold: Even consumption below the 21/14 drinks per week threshold contributes to liver fat, and any alcohol use in NAFLD patients doubles the risk of adverse liver outcomes 1