What is the pathophysiology and management of alcoholic liver disease?

Pathophysiology of Alcoholic Liver Disease

Alcoholic liver disease progresses through distinct pathophysiological stages—from simple steatosis to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma—driven by metabolic derangements, oxidative stress, inflammatory cascades, and gut-liver axis disruption. 1

Disease Spectrum and Natural History

The clinical spectrum encompasses fatty liver (steatosis), alcoholic steatohepatitis, progressive fibrosis, cirrhosis, and hepatocellular carcinoma. 1 While 80-90% of heavy drinkers develop steatosis, only 10-20% progress to cirrhosis, with genetic and environmental factors modifying individual susceptibility. 1 Continued alcohol consumption ≥400 g/week increases cirrhosis risk to 30% and fibrosis/cirrhosis risk to 37%. 1

Stage 1: Alcoholic Fatty Liver (Steatosis)

Steatosis develops through four interconnected metabolic mechanisms:

Metabolic Derangements

• Increased NADH generation from alcohol oxidation favors fatty acid and triglyceride synthesis while inhibiting mitochondrial β-oxidation of fatty acids. 1
• Enhanced hepatic influx of free fatty acids from adipose tissue and chylomicrons from intestinal mucosa into the liver. 1
• AMPK pathway suppression by ethanol results in increased lipogenesis through SREBP1c activation and decreased lipolysis through PPARα inhibition. 1
• Acetaldehyde-induced organelle damage to mitochondria and microtubules reduces NADH oxidation and causes VLDL accumulation. 1

This stage is reversible with abstinence, but continued drinking drives progression. 1

Stage 2: Alcoholic Steatohepatitis

Steatohepatitis represents the critical transition point where inflammation and hepatocellular injury enable progression to fibrosis and cirrhosis. 1 This stage features polymorphonuclear leukocyte infiltration, hepatocyte injury, and is necessary for fibrosis development. 1

Acetaldehyde Toxicity

Ethanol metabolism via alcohol dehydrogenase (cytosol), CYP450 (microsomes), and catalase (peroxisomes) generates acetaldehyde, which:

• Binds to proteins and DNA, creating functional alterations and protein adducts that act as autoantigens, activating immune responses. 1
• Induces mitochondrial damage and impairs glutathione function, leading to oxidative stress and apoptosis. 1
• Decreases mitochondrial glutathione and S-adenosyl-L-methionine levels, sensitizing hepatocytes to injury. 1

Oxidative Stress Cascade

Reactive oxygen species generation occurs through multiple pathways:

• CYP2E1 upregulation by chronic alcohol intake metabolizes ethanol to acetaldehyde while generating ROS and hydroxyl-ethyl radicals. 1
• Additional ROS sources include mitochondrial electron transport chain, NADH-dependent cytochrome reductase, and xanthine oxidase. 1
• Lipid peroxidation with DNA adduct formation results from ROS generation. 1

Pro-Inflammatory Cytokine Activation

Alcohol metabolites and ROS activate multiple inflammatory signaling pathways:

• NFκB, STAT-JAK, and JNK pathways in hepatic resident cells drive local synthesis of TNF-α, IL-17, CXC chemokines (IL-8), and osteopontin. 1
• Gut-liver axis disruption occurs as alcohol abuse alters colonic microbiota and increases intestinal permeability. 1
• Elevated lipopolysaccharide levels trigger inflammatory responses in Kupffer cells via CD14/TLR4 pathway. 1
• Resulting inflammatory milieu causes PMN infiltration, ROS formation, and hepatocellular damage. 1

Impaired Protein Degradation

Dysfunction of the ubiquitin-proteasome pathway leads to hepatocellular injury and hepatic inclusions of aggregated proteins. 1

Stage 3: Fibrosis and Cirrhosis

Liver fibrosis represents a wound-healing response characterized by excessive extracellular matrix protein accumulation, particularly collagen. 1 Fibrosis occurs in alcoholic steatohepatitis and accelerates with chronic inflammation. 1

Long-term excessive drinking confers a 15-30% lifetime risk of cirrhosis. 1 Even with abstinence, 5-15% of patients may still develop fibrosis or cirrhosis, indicating that abstinence alone does not guarantee disease resolution. 1

Clinical Outcomes and Prognosis

Severe Alcoholic Hepatitis

Severe episodes cause profound liver damage, increased portal resistance, and carry a 1-month mortality of 40%. 1 More than 50% of symptomatic patients present with concomitant cirrhosis. 1

Decompensated Cirrhosis

At cirrhosis diagnosis, 55% present with ascites alone, 24% without complications, 6% with variceal bleeding alone, 4% with combined ascites and variceal bleeding, and 11% with hepatic encephalopathy. 1 The 1-year decompensation rate is 37.6% for alcoholic cirrhosis versus 25.2% for non-alcoholic cirrhosis. 1

Mortality and Hepatocellular Carcinoma

The 5-year survival rate for compensated cirrhosis approaches 90% with abstinence but drops below 70% with continued drinking. 1 For decompensated cirrhosis, 5-year survival is 60% with abstinence versus 30% with continued drinking. 1 HCC incidence is 7.2-16.0% in alcoholic cirrhosis, with 1% annual risk in decompensated disease. 1

Critical Pathophysiological Concepts

The mechanisms are incompletely understood because animal models only induce moderate liver disease, not the severe fibrosis and damage seen in humans. 1 Translational studies using human liver samples are essential for developing targeted therapies. 1

Genetic and non-genetic factors significantly modify individual susceptibility and clinical course, explaining why only a minority progress from steatosis to advanced disease despite similar alcohol exposure. 1