What is the pathophysiological mechanism by which alcohol misuse leads to alcoholic hepatitis?

Pathophysiological Mechanism of Alcoholic Hepatitis from Alcohol Misuse

Alcohol misuse leads to alcoholic hepatitis through multiple complex pathways involving direct hepatotoxicity, oxidative stress, inflammatory responses, and gut-liver axis disruption that collectively damage hepatocytes and trigger inflammatory cascades in the liver. 1

Initial Liver Changes: Alcoholic Fatty Liver (Steatosis)

Steatosis is the initial reaction to alcohol abuse, characterized by fat accumulation in hepatocytes through four primary mechanisms:

1. Altered metabolism and oxidation:

   • Alcohol oxidation increases nicotinamide adenine dinucleotide (NADH), triglycerides, and fatty acids
   • Suppression of mitochondrial β-oxidation occurs
   • Acetaldehyde (alcohol metabolite) damages mitochondria and microtubules 1

2. Increased lipid influx to liver:

   • Enhanced influx of free fatty acids from adipose tissue
   • Increased chylomicrons from visceral mucosa 1

3. Dysregulation of lipid metabolism pathways:

   • Suppression of adenosine-monophosphate-activated protein kinase (AMPK)
   • Increased lipid biosynthesis
   • Suppression of peroxisome proliferator-activated receptor α (PPARα)
   • Decreased lipolysis due to sterol regulatory element binding protein 1c (SREBP1c) activation 1

4. Impaired lipid export:

   • Decreased NADH oxidation
   • Accumulation of very-low-density lipoprotein (VLDL) 1

Progression to Alcoholic Hepatitis

Alcoholic hepatitis develops through several key mechanisms:

1. Acetaldehyde Toxicity and Oxidative Stress

• Ethanol is metabolized to acetaldehyde by alcohol dehydrogenase (ADH), P450 enzymes, and catalase
• Acetaldehyde:
  • Combines with proteins and DNA to create abnormal compounds
  • Alters protein function and synthesis
  • Creates auto-antigens that activate the immune system
  • Causes oxidative stress through mitochondrial damage
  • Impairs glutathione function 1, 2

2. Pro-inflammatory Cascade

• Alcohol metabolites and oxygen free radicals activate signaling pathways:
  • Nuclear factor-κB (NFκB)
  • Signal transducer and activator of transcription-Janus kinase (STAT-JAK)
  • c-Jun N-terminal kinase (JNK)
• These pathways induce inflammatory mediators:
  • Tumor necrosis factor-α (TNF-α)
  • Interleukin-17 (IL-17)
  • CXC chemokines
  • Osteopontin 1

3. Gut-Liver Axis Disruption

• Alcohol disrupts normal intestinal microbiota
• Increases intestinal permeability to bacterial endotoxins
• Elevated serum lipopolysaccharide levels
• Activation of Kupffer cells via CD14/toll-like receptor 4 (TLR4) pathway
• Inflammatory cell infiltration, particularly polymorphonuclear leukocytes 1, 2

4. Systemic Inflammatory Response

• Features of systemic inflammatory response syndrome (SIRS) often present:
  • Tachycardia
  • Tachypnea
  • Fever
  • Leukocytosis 1

Risk Factors for Alcoholic Hepatitis

Several factors increase susceptibility to alcoholic hepatitis:

• Female gender
• Elevated body mass index (BMI)
• Genetic factors (e.g., G allele of PNPLA3)
• Continued heavy alcohol consumption (>50g/day)
• Obesity and metabolic syndrome 1

Clinical Progression and Outcomes

Without abstinence from alcohol, the disease can progress:

• Alcoholic fatty liver → Alcoholic hepatitis → Alcoholic cirrhosis
• Continued alcohol use (≥400g/week) increases risk of progression to cirrhosis (30%) and fibrosis or cirrhosis (37%)
• Severe alcoholic hepatitis has high short-term mortality if untreated 1

Histological Features

Characteristic findings in alcoholic hepatitis include:

• Steatosis and ballooning degeneration of hepatocytes
• Intrahepatic cholestasis (bilirubinostasis)
• Chicken-wire fibrosis
• Mallory-Denk bodies
• Megamitochondria
• Cirrhosis (present in most severe cases) 1

Understanding these pathophysiological mechanisms is crucial for developing effective treatments and improving outcomes for patients with alcoholic hepatitis.