What is the pathophysiology of hepatic steatosis?

Pathophysiology of Hepatic Steatosis

Hepatic steatosis develops when intrahepatic fat accumulation exceeds 5% of liver weight, driven primarily by an imbalance between lipid acquisition (increased fatty acid influx and de novo lipogenesis) and lipid disposal (impaired β-oxidation and VLDL secretion). 1

Core Metabolic Mechanisms

The pathophysiology operates through four interconnected pathways that converge to produce fat accumulation in hepatocytes:

1. Increased Fatty Acid Delivery

• Enhanced influx of free fatty acids from adipose tissue and chylomicrons from the intestinal mucosa directly to the liver 2
• This represents the dominant source of hepatic triglycerides in most patients with metabolic dysfunction 1

2. Enhanced De Novo Lipogenesis

• Alcohol oxidation increases NADH synthesis, which drives triglyceride and fatty acid production while simultaneously suppressing mitochondrial β-oxidation 2
• Ethanol-mediated suppression of AMPK activation results in increased lipid biosynthesis 2
• Activation of SREBP1c further amplifies lipogenesis while suppression of PPARα decreases lipolysis 2

3. Impaired Lipid Clearance

• Reduced hepatic β-oxidation capacity limits fatty acid catabolism 1
• Acetaldehyde-induced mitochondrial and microtubule damage decreases NADH oxidation and causes VLDL accumulation 2
• Diminished VLDL secretion prevents triglyceride export from hepatocytes 1

4. Mitochondrial Dysfunction

• Prolonged lipid storage leads to mitochondrial impairment, creating a vicious cycle of reduced oxidative capacity 1
• This dysfunction represents a critical transition point from simple steatosis to more advanced liver injury 1

Histologic Patterns and Clinical Significance

Macrovescicular vs. Microvescicular Steatosis

• Macrovescicular steatosis involves large lipid droplets occupying the entire cytoplasm and is characteristically associated with alcohol, obesity, and diabetes 2
• Microvescicular steatosis consists of tiny lipid droplets (<1 mm) creating a foamy cytoplasmic appearance, associated with drug toxicity, acute fatty liver of pregnancy, and Reye syndrome 2
• Macrovescicular steatosis carries greater clinical significance for disease progression, while microvescicular patterns typically do not preclude organ function 2

Disease Spectrum and Progression

Simple Steatosis (NAFL)

• Represents 70-75% of NAFLD/MASLD cases 3, 4
• Defined by hepatic steatosis without hepatocellular injury or ballooning 2
• Most patients remain asymptomatic and exhibit very slow or absent histological progression 2
• The fat accumulation itself may be hepatoprotective in the absence of additional cellular insults 1

Steatohepatitis (NASH/MASH)

• Occurs in 25-30% of cases and represents a critical pathophysiologic transition 3, 4
• Characterized by hepatic steatosis plus inflammation with hepatocyte injury (ballooning), with or without fibrosis 2
• Multiple factors drive this progression: acetaldehyde toxicity, oxygen free radical production, and inflammatory cell infiltration (predominantly polymorphonuclear leukocytes) 2
• Patients with steatohepatitis can exhibit histological progression to cirrhotic-stage disease 2

Metabolic Context and Risk Factors

• NAFLD/MASLD is intrinsically linked to metabolic risk factors including obesity, type 2 diabetes, and dyslipidemia 2
• The prevalence reaches 70% in obesity and 90% in diabetes 3
• This metabolic dysfunction creates a systemic environment that perpetuates hepatic lipid accumulation through insulin resistance and dysregulated adipokine signaling 5

Key Clinical Pitfall

The majority (60-80%) of patients with chronic hepatic steatosis remain completely asymptomatic because simple steatosis occurs without cellular injury or inflammation 4. The liver capsule lacks pain receptors for stretch or fat accumulation alone; symptoms typically require inflammation (steatohepatitis), rapid enlargement, or progression to fibrosis and cirrhosis 4. This silent nature makes early detection challenging and underscores the importance of screening high-risk populations despite normal liver biochemistries 2.