What are the causes and treatment options for fatty liver disease in patients with obesity, insulin resistance, and metabolic syndrome?

Causes of Fatty Liver Disease

Primary Causes

The two most common causes of fatty liver disease are nonalcoholic fatty liver disease (NAFLD) and alcohol-induced steatosis/steatohepatitis. 1

Nonalcoholic Fatty Liver Disease (NAFLD)

NAFLD is directly related to insulin resistance and metabolic syndrome, representing the hepatic manifestation of systemic metabolic dysfunction. 1 The disease affects 20-30% of the general population in developed countries, but this prevalence increases dramatically to 70% in patients with obesity and 90% in those with diabetes mellitus. 1

Key metabolic risk factors include:

• Obesity and visceral adiposity - Excessive BMI is the most well-documented risk factor, with prevalence exceeding 90% in severely obese patients undergoing bariatric surgery. 2
• Type 2 diabetes mellitus - Carries a 60-75% prevalence of NAFLD and is a major risk factor for disease progression to NASH and worse liver outcomes. 1, 2
• Insulin resistance - This is the pathophysiological hallmark of NAFLD, characterized by reduced whole-body, hepatic, and adipose tissue insulin sensitivity. 3
• Metabolic syndrome - Confers a 50% prevalence of NAFLD, with 40.7% of Korean NAFLD patients having metabolic syndrome. 1, 2
• Dyslipidemia - High serum triglycerides and low HDL cholesterol are very common in NAFLD patients. 2

Alcohol-Induced Fatty Liver Disease

Excessive alcohol consumption results in alcohol-induced fatty liver disease, which can be distinguished from NAFLD by the AST:ALT ratio (generally >2 in alcohol-induced disease versus <1 in metabolic disease-related fatty liver). 1 The definition requires ingestion of >21 standard drinks per week in men and >14 standard drinks per week in women over a 2-year period. 1

Secondary Causes

Other causes of fatty liver include:

• Medications - Corticosteroids, amiodarone, methotrexate, tamoxifen, and valproate are associated with secondary hepatic steatosis and should be avoided when possible. 2
• Viral hepatitis - Hepatitis B and hepatitis C are uncommon causes of mild aminotransferase increases. 1
• Hereditary conditions - Alpha1-antitrypsin deficiency, Wilson disease, and hereditary hemochromatosis are rare causes. 1
• Acute conditions - Acute Budd-Chiari syndrome and ischemic hepatitis can cause hepatocellular injury. 1

Demographic and Lifestyle Risk Factors

Age and gender:

• NAFLD prevalence increases progressively with age. 2
• Male gender is an independent risk factor for fatty liver disease. 2
• Hispanic individuals have significantly higher prevalence compared to non-Hispanic whites. 2

Lifestyle factors:

• Decreased physical activity and sedentary lifestyle increase both prevalence and incidence of NAFLD, independent of other metabolic factors. 2
• Diets rich in saturated fatty acids, sugar-sweetened beverages, refined carbohydrates, fructose, and high caloric intake promote both obesity and NAFLD. 1

Endocrine and Metabolic Disorders

• Hypothyroidism - Increases NAFLD prevalence by 1.6 times. 2
• Polycystic ovary syndrome - Increases incidence approximately 2.2 times. 2
• Hypogonadism - An independent risk factor for NAFLD. 2
• Sarcopenia - Increases NAFLD risk approximately four-fold, independent of obesity or metabolic syndrome. 2

Genetic Factors

PNPLA3 and TM6SF2 gene variants significantly affect disease development, progression, and severity. 2 In Korea, PNPLA3 and SAMM50 were associated with both prevalence and severity of NAFLD. 1

Pathophysiological Mechanisms

The accumulation of fat in the liver occurs through multiple mechanisms:

• Excess dietary fat intake 3
• Increased delivery of free fatty acids to the liver 3
• Inadequate fatty acid oxidation 3
• Increased de novo lipogenesis 3
• Gut microbiota dysbiosis, which is characterized by decreased microbial gene richness in obesity and is associated with proinflammatory status 1

Treatment Approach Based on Causes

For metabolic-associated fatty liver disease:

• Target 7-10% weight loss through Mediterranean diet with 500-1,000 kcal/day deficit and 150-300 minutes weekly moderate-intensity exercise. 1
• Treat underlying diabetes with GLP-1 receptor agonists (semaglutide, liraglutide) which improve both glycemic control and liver histology. 1
• Manage dyslipidemia with statins, which are safe in fatty liver disease and reduce hepatocellular carcinoma risk by 37%. 1

For alcohol-induced disease:

• Complete alcohol abstinence is mandatory, as even 9-20g daily doubles risk of adverse liver outcomes. 1

Critical Screening Recommendations

Screening should be prioritized in:

• Patients with type 2 diabetes, regardless of liver enzyme levels 1, 2
• Patients with persistent liver enzyme elevation 1
• Patients with two or more metabolic risk factors 2
• Patients with metabolic syndrome, obesity, and insulin resistance 1

Abdominal ultrasonography is the primary screening modality, with sensitivity of 84.8% and specificity of 93.6% for moderate and severe hepatic fat deposition (>30% by histology). 1