The pathogenesis of alcoholic liver disease is complex and still remains unclear, the metabolites of the oxidative metabolism in the liver; acetaldehyde and reactive oxygen species are thought to be involved in the toxic effects of ethanol on the liver.

• Ethanol metabolism in the liver is carried out mainly by two enzymes:^[1]
  • Alcohol dehydrogenase
  • Aldehyde dehydrogenase
• Both of these enzymes use NAD+ as a cofactor. Alcohol is converted to acetaldehyde and acetaldehyde is then further oxidized to acetate. Acetaldehyde is the toxic metabolite in this process.
• The metabolism of alcohol in the liver ends up producing an excess of reduced nicotinamide adenine dinucleotide (NADH). This changes the reduction–oxidation potential in the liver and inhibits key metabolic processes in the liver such as, the tricarboxylic acid cycle and the oxidation of fatty acids and thereby ends up promoting lipogenesis.^[2]
• Since acetaldehyde has an electrophilic nature it can form covalent chemical bonds with proteins, lipids and DNA. These covalent bonds that are formed are extremely pathogenic, as they have the ability to alter cell environments, protein structures and they can enable DNA damage and mutation.^{[3][4][5][6][7][8][9][10]}

• The cytochrome P450 enzymes (CYP) are a part of the microsomal ethanol oxidizing system. These are a large group of enzymes involved in numerous oxidizing reactions on different substrates. They catalyze many different reactions in order to make them in to more polar metabolites that are easier to excrete.^[11]

• There is an ethanol inducible form of CYP enzymes that is working in a small amount under normal physiological conditions. This enzyme CYP2E1 is converting ethanol to acetaldehyde and then to acetate. When there is chronic alcohol abuse, there is induction of the microsomal system and there is an increase in the expression of CYP2E1. This increase in CYP2E1 expression under chronic ethanol consumption can be hazardous, as this oxidation reaction can produces many different ROS; O₂^–, H₂O₂, OH^– and hydroxyethyl radical (HER).^{[12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]}

• Ethanol metabolism additionally promotes lipogenesis through the inhibition of peroxisome proliferator activated receptor α (PPAR-α) and AMP kinase, as well as the stimulation of sterol regulatory element binding protein 1, which is a membrane bound transcription factor. The sequence of all these events results in a fat storing metabolic remodeling of the liver.^[28][29][30]

• Two key factors that play an important role in the inflammatory process that leads to the alcohol mediated liver injury are:^[31][32]
  • Endotoxin
  • Gut permeability
• Endotoxin is associated to the lipopolysaccharide (LPS) component of the outer wall of gram-negative bacteria and is thought to be the key trigger in this inflammatory process.^[33][34]
• Gut permeability is the factor that is either enabling or preventing the transfer of the LPS-endotoxin from the intestinal lumen into the portal circulation.^[35][36]
• The fact that long term exposure to alcohol increases gut permeability has been observed in humans as LPS-endotoxin levels have been found to be elevated in patients with alcoholic liver injury.^[37]

• After the entry of LPS-endotoxin in to the portal circulation it binds to the LPS-binding protein, this is a key step in the inflammatory and histopathological response to alcohol ingestion.^[38]
• The LPS-LPS binding protein complex binds to the CD14 receptor on the cell surface membrane of the Kupffer cells in the liver.
• Activation of these Kupffer cells requires 3 main cellular proteins:^[39]
  • CD14 (monocyte differentiation antigen)^[40]
  • Toll-like receptor 4 (TLR4)^[41]
  • MD2, a protein, binds TLR4 with LPS-LPS binding protein
• The TLR4 then signals activation of early growth response 1 (EGR1), which is an early gene-zinc-finger transcription factor.^[42]
• The nuclear factor-kB (NF-kB) and the TLR4 adapter also play an important role in the activation of the kupffer cells.^[43]
• EGR1 plays the pivotal role in lipopolysaccharide-stimulated TNF-α production.
• In mice the absence of EGR1 prevents alcohol induced liver injury.^[44]

• Ethanol administration stimulates the release of mitochondrial cytochrome c and the expression of the Fas ligand, this leads to hepatic cell apoptosis mediated by the cascade-3 activation pathway.^[45]
• The cumulative effect of TNF-α and Fas-mediated apoptotic signals make the hepatocytes more susceptible to injury by stimulating an increase in natural killer T cells in the liver.^[46]

• Susceptibility to alcoholic liver disease could be determined by functional polymorphisms in the ADH2 gene.^[47][48]

• Polymorphism at position -238 of the TNF-α promoter region.^[49][50]

Conditions associated with alcoholic liver disease include:^[1][51]

• Obesity
• Chronic viral hepatitis
• Iron overload
• Cirrhosis
• Hepatocellular carcinoma

• On gross pathology, characteristic findings of alcoholic liver disease include:^[52]
  • Hepatomegaly
  • Nodules
    • Macronodules
    • Micronodules
  • Firm in consistency
  • Portal vein dilation

On microscopic histopathological analysis characteristic findings of alcoholic liver disease include:^{[53][54][55][56][57][58][59][60]}

• Non-cirrhotic liver
  • Steatosis
    • Macrovesicular steatosis – the cytoplasm of hepatocytes is occupied by large lipid droplets that end up displacing the nucleus and other organelles peripherally
  • Proliferation of the smooth endoplasmic reticulum
  • Distortion of the mitochondria (giant mitochondria)
  • Hepatocyte balooning (Mallory-Denk bodies)

• Cirrhotic liver:
  • Fibrous septae that are made up of collagen surrounding the hepatocytes which results in pseudo lobule formation.
  • This produces a nodular appearance of the liver and then progresses from micro nodular to macro nodular cirrhosis with time.
  • Proliferation of the bile ducts may also be seen.