What is the pathogenesis of steatohepatitis, specifically non-alcoholic steatohepatitis (NASH)?

Pathogenesis of Steatohepatitis

The pathogenesis of steatohepatitis, particularly non-alcoholic steatohepatitis (NASH), is primarily driven by lipotoxicity where free fatty acid metabolites cause endoplasmic reticular stress, hepatocyte apoptosis, necrosis, and inflammation, leading to characteristic histologic findings and disease progression. 1

Fundamental Mechanisms

Initial Fat Accumulation (Steatosis)

• Occurs through multiple mechanisms:
  • Excess energy intake leading to increased hepatic lipid storage as triglycerides 1
  • De novo lipogenesis in the liver 1
  • Decreased export of triglycerides from the liver as very-low density lipoproteins 1
  • In alcoholic steatohepatitis: ethanol metabolism leads to increased NADH, triglycerides, and fatty acids, with suppressed mitochondrial β-oxidation 1

From Simple Steatosis to Steatohepatitis

The progression from simple steatosis to steatohepatitis involves several key processes:

1. Lipotoxicity Model (Current Leading Theory):

   • Free fatty acid metabolites (not triglycerides themselves) cause cellular injury 1
   • These metabolites trigger endoplasmic reticular stress 1
   • Result: hepatocyte apoptosis, necrosis, and inflammation 1
   • Notably, triglyceride accumulation may actually be protective against hepatocellular injury 1

2. Older "Two-Hit" Hypothesis:

   • First hit: fat accumulation in hepatocytes
   • Second hit: oxidative stress leading to lipid peroxidation and necroinflammatory injury 1

Cellular and Molecular Mechanisms

Oxidative Stress and Inflammation

• In alcoholic steatohepatitis:
  • Alcohol metabolites and oxygen free radicals activate NFκB, STAT-JAK, and JNK pathways 1
  • These pathways induce production of inflammatory mediators (TNF-α, IL-17, CXC chemokines, osteopontin) 1
  • Alcohol disrupts intestinal microbiota and increases gut permeability 1
  • Increased serum lipopolysaccharide levels trigger inflammatory reactions in Kupffer cells via CD14/TLR4 pathway 1

Genetic Factors

• PNPLA3 gene variant I148M (rs738409) is strongly associated with:
  • Increased hepatic fat content 1
  • Hepatic inflammation 1
  • Higher frequency in Hispanic patients, explaining increased susceptibility 1
• Other genetic variants affecting hepatocyte lipid droplet homeostasis have been identified 1

Metabolic Factors

• Strong correlation between NASH and:
  • Obesity
  • Diabetes
  • Metabolic syndrome 1
• Insulin resistance plays a critical role:
  • Favors accumulation of free fatty acids in the liver
  • Promotes oxidative stress by stimulating microsomal lipid peroxidases 1

Histopathological Features

NASH is characterized by specific histological findings:

• Macrovesicular steatosis (≥5% hepatic steatosis) 2
• Lobular inflammation 2
• Hepatocellular injury (primarily hepatocyte ballooning) 2
• With or without fibrosis 2
• Additional features often include:
  • Acidophil bodies (apoptotic hepatocytes) 1
  • Mallory-Denk bodies (damaged intermediate filaments) 1

Disease Progression

• NASH occurs in approximately 20% of patients with NAFLD (3-12% of US population) 1, 2
• About 30-40% of NASH patients will develop fibrosis 1, 2
• NASH is the third leading cause of cirrhosis in the US 1
• Third most common indication for liver transplantation 1, 2

Clinical Implications

Understanding the pathogenesis of steatohepatitis has important implications:

1. Therapeutic Targets:

   • Genetically validated targets like PNPLA3 and HSD17B13 are being explored in clinical trials 1
   • FXR (farnesoid X receptor) has emerged as a target of interest due to its role in metabolism and insulin sensitivity 1

2. Risk Stratification:

   • Metabolic syndrome, diabetes, and advanced age increase risk of liver disease progression 1
   • Genetic testing may help identify patients at higher risk for disease progression

Common Pitfalls in Understanding Steatohepatitis Pathogenesis

• Misconception: Triglyceride accumulation itself causes liver injury

  • Reality: Triglyceride accumulation may actually be protective; free fatty acid metabolites are the primary drivers of cellular injury 1

• Misconception: NASH is simply "fatty liver disease"

  • Reality: NASH specifically requires inflammation and hepatocellular injury (ballooning) in addition to steatosis 2

• Misconception: Alcoholic and non-alcoholic steatohepatitis have completely different pathogenesis

  • Reality: Many genetic variants associated with NAFLD are also associated with alcohol-related fatty liver disease, suggesting overlapping mechanisms 1