What are the causes and management of fatty liver disease?

Causes of Fatty Liver Disease

Primary Metabolic Causes

The two most common causes of fatty liver disease are non-alcoholic fatty liver disease (NAFLD) driven by metabolic dysfunction and alcohol-induced steatosis/steatohepatitis. 1

Non-Alcoholic Fatty Liver Disease (NAFLD)

• Obesity is the strongest risk factor, present in 70% of NAFLD cases and reaching 90% prevalence in patients with diabetes mellitus. 1
• Type 2 diabetes and insulin resistance are primary drivers, with NAFLD present in 30-40% of the general US population and significantly higher in diabetic populations. 2
• Metabolic syndrome components including dyslipidemia, hypertension, and central adiposity collectively promote hepatic steatosis through insulin resistance mechanisms. 1, 2
• The AST:ALT ratio is typically <1 in metabolic disease-related fatty liver, distinguishing it from alcoholic causes. 1

Alcohol-Induced Fatty Liver Disease

• Excessive alcohol consumption defined as >21 standard drinks/week in men or >14 drinks/week in women causes alcohol-induced steatosis. 2
• The AST:ALT ratio is generally >2 in alcohol-induced fatty liver disease, a key diagnostic distinction. 1
• Complete abstinence is required for patients with alcohol-related liver disease to prevent progression to cirrhosis and liver-related mortality. 1, 3

Secondary Causes That Must Be Excluded

Medications

• Steatogenic medications include amiodarone, methotrexate, tamoxifen, and corticosteroids, which directly cause hepatic fat accumulation. 2
• A comprehensive medication review is mandatory in all patients presenting with fatty liver. 2

Viral Hepatitis

• Hepatitis C genotype 3 directly causes hepatic steatosis independent of metabolic factors. 2
• Chronic viral hepatitis must be systematically excluded through serologic testing. 2

Hereditary and Monogenic Disorders

• In very young children or non-overweight individuals, consider fatty acid oxidation defects, lysosomal storage diseases, peroxisomal disorders, and cystic fibrosis. 1
• Alpha-1 antitrypsin deficiency, Wilson disease, and hemochromatosis are rare but important causes requiring specific testing. 1, 2

Demographic and Genetic Risk Factors

Age and Sex

• NAFLD prevalence increases with age, with older patients facing higher risk of progression to advanced fibrosis. 2
• Men have approximately twice the prevalence of NAFLD compared to women. 2

Ethnicity

• Hispanic individuals have significantly higher prevalence of NAFLD compared to other ethnic groups. 2
• Non-Hispanic blacks have lower prevalence compared to non-Hispanic whites. 2

Genetic Variants

• PNPLA3 I148M, TM6SF2 E167K, and other genetic variants increase susceptibility to steatosis, inflammation, fibrosis, and hepatocellular carcinoma risk. 2
• Family members of children with NAFLD show much higher likelihood of exhibiting abnormally high liver fat fractions. 1

Diagnostic Approach to Identify Causes

Alcohol Assessment

• Use sensitive biomarkers including urine ethyl glucuronide and blood phosphatidylethanol if under-reporting of alcohol consumption is suspected. 2
• Standard alcohol history questionnaires are essential but may be unreliable without biochemical confirmation. 2

Exclude Competing Liver Diseases

• Test for hemochromatosis, autoimmune hepatitis, chronic viral hepatitis, alpha-1 antitrypsin deficiency, and Wilson disease through appropriate serologic and biochemical panels. 2
• Low serum titers of autoantibodies are common in NAFLD, but higher titers with elevated aminotransferases and globulin should prompt liver biopsy to exclude autoimmune hepatitis. 1

Metabolic Risk Factor Assessment

• Evaluate diabetes status, lipid panel, BMI, and all metabolic syndrome components as these directly correlate with NAFLD presence and severity. 2
• Liver fat correlates linearly with all components of metabolic syndrome independent of obesity. 4

Imaging for Initial Evaluation

• Ultrasound is the first-line investigation for mild aminotransferase elevation, with 84.8% sensitivity and 93.6% specificity for moderate-to-severe steatosis (>30% hepatic fat). 1
• Ultrasound sensitivity declines to 53.3-65% for mild steatosis, and specificity deteriorates with concurrent inflammation or fibrosis. 1

Management Principles Based on Etiology

For NAFLD

• Weight loss of 7-10% through caloric restriction and regular physical activity improves liver histology, reduces inflammation, and can improve fibrosis. 3
• All NAFLD patients require lifestyle modifications and treatment of comorbidities regardless of disease severity. 1
• Patients with NASH or hepatic fibrosis need pharmacologic treatment for histologic improvement. 1

For Alcohol-Induced Disease

• Complete and permanent abstinence is the cornerstone of treatment for alcoholic liver disease. 3
• Patients with cirrhosis must abstain completely as continued drinking increases HCC risk and liver-related mortality. 1

Risk Factor Modification

• Smoking cessation, alcohol abstinence, and weight loss are recommended to reduce HCC development in NAFLD patients. 1
• Diabetes control with metformin decreases HCC incidence, while sulfonylurea and insulin use increase HCC risk. 1