What are the etiologies of hepatic steatosis?

What Causes Fatty Liver

Fatty liver results from an imbalance between lipid acquisition (from plasma free fatty acids and de novo lipogenesis) and lipid disposal (through oxidation and VLDL secretion), driven primarily by insulin resistance in the setting of metabolic dysfunction. 1, 2

Primary Metabolic Mechanisms

The accumulation of hepatic triglycerides occurs through several interconnected pathways:

Lipid Acquisition Pathways

• Plasma free fatty acids (FFA) from adipose tissue lipolysis represent the largest contributor, accounting for 50-70% of hepatic triglycerides in the fasted state 3
• De novo lipogenesis (DNL) is markedly elevated—approximately 5-fold higher in fatty liver compared to normal individuals 3
• Dietary chylomicrons from intestinal absorption deliver fatty acids directly to the liver 1, 2

The Central Role of Insulin Resistance

Insulin resistance serves as the central metabolic driver linking adipose tissue dysfunction to hepatic fat accumulation 2, 4:

• Inadequate suppression of FFA release from adipose tissue in the postprandial period leads to excessive fatty acid flux to the liver 3
• Hyperinsulinemia paradoxically promotes transcriptional upregulation of lipogenic genes despite systemic insulin resistance 5
• This creates a "double hit" where both fatty acid delivery increases and hepatic lipid synthesis accelerates simultaneously 5

Impaired Lipid Disposal

• Fatty acid oxidation fails to compensate for increased lipid availability 6, 5
• VLDL secretion is increased but insufficient to prevent triglyceride accumulation, despite larger VLDL particle size 3
• The liver cannot adequately export the excess triglycerides being synthesized and delivered 7

Major Risk Factors and Associated Conditions

Metabolic Syndrome Components

Fatty liver is strongly associated with metabolic syndrome components 1, 2:

• Obesity: Prevalence reaches 70% in obese individuals 3, 4
• Type 2 diabetes: Prevalence exceeds 70% and reaches 90% in diabetic patients 3, 4
• Dyslipidemia: Elevated fasting triglycerides, elevated LDL, and low HDL are common 3
• Hypertension: Part of the metabolic syndrome cluster 1, 2

Dietary Factors

Dietary fructose represents a highly lipogenic sugar that potentiates fatty liver through multiple mechanisms 3:

• Fructose is cleared from blood on first pass through the liver and metabolized relatively unregulated by insulin 3
• Fructose consumption stimulates DNL and may increase liver fibrosis severity 3
• Fructose may alter the gut microbiome and increase intestinal permeability to endotoxin, promoting hepatic inflammation 3

Alcohol

Alcohol oxidation increases NADH synthesis, which drives triglyceride and fatty acid production while suppressing mitochondrial β-oxidation 4:

• Ethanol-mediated suppression of AMPK activation increases lipid biosynthesis 4
• Activation of SREBP1c amplifies lipogenesis while suppression of PPARα decreases lipolysis 4
• Acetaldehyde-induced mitochondrial damage decreases NADH oxidation and causes VLDL accumulation 4

Genetic Factors

The PNPLA3 I148M variant (rs738409) is associated with increased hepatic fat content and inflammation 3:

• This allele is found at higher frequency in Hispanic patients, providing one explanation for increased susceptibility in this population 3
• Family history of diabetes represents an independent risk factor 3

Secondary Causes to Exclude

When diagnosing fatty liver, exclude significant alcohol consumption (>21 standard drinks per week in men, >14 in women over 2 years) and other secondary causes 3, 2:

• Long-term steatogenic medications 2
• Hepatitis C virus genotype 3 infection 7
• Certain medications causing drug-induced steatosis 4

Clinical Significance and Disease Spectrum

Simple steatosis (≥5% hepatic fat without injury) represents 70-75% of cases and carries minimal progression risk 1, 2, 4:

• Most patients remain asymptomatic (60-80%) because the liver capsule lacks pain receptors for fat accumulation alone 2, 4

Steatohepatitis (steatosis plus inflammation with hepatocyte ballooning) occurs in 25-30% of cases and represents a critical transition with higher risk of progression to cirrhosis, liver failure, and hepatocellular carcinoma 1, 2, 4

Common Pitfalls

• Clinicians underestimate the prevalence of fatty liver in high-risk populations like obesity and type 2 diabetes, missing opportunities for early intervention 3
• The asymptomatic nature of early disease means screening must be proactive in metabolic risk populations rather than symptom-driven 2, 4
• Elevated transaminases are not required for diagnosis—many patients have normal liver biochemistries despite significant steatosis 4