Alcoholic hepatitis pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shadan Mehraban, M.D.[2]Prashanth Saddala M.B.B.S

The pathophysiology of Alcoholic Hepatitis is caused by interplay between alcohol metabolism, inflammation and innate immunity. Alcohol metabolism leads to depletion of NAD and subsequent lipogenesis. Additionally, increased endotoxemia causes translocation of lipopolysaccharide from intestine to hepatocytes. In hepatocytes, lipopolysaccharide activates kupffer cells. Therefore, activated cells release inflammatory markers which lead to Alcoholic hepatitis.

• The pathogenesis of Alcoholic Hepatitis is multifactorial.
  • Alcoholic Hepatitis is caused by interplay between alcohol metabolism, inflammation and innate immunity. ^[1]
• Ethanol metabolism in the liver is carried out mainly by two enzymes:^[2]
  • 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 Alcohol metabolism leads to a reduced ratio of the nicotinamide adenine dinucleotide (NAD) to NADH. The NAD depletion inhibit fatty acid oxidation and causes fat accumulation in hepatocytes associated with lipogenesis. ^[1]
• Due to increased intestinal permeability in patients with Alcoholic Hepatitis, high levels of Endotoxemia is recognized.^[1]
  • Endotoxin binds to lipopolysaccharide and translocate from intestine to hepatocytes.^[3]
  • In hepatocytes, lipopolysaccharide bindes to CD14 molecule and toll-like receptor 4 on surface of Kupffer cells.^[4]
  • These bindings activate Kupffer cells to release reactive oxygen species.^[3]
• This activation release tumor necrosis factor-alpha (TNF alpha), interleukin-8, monocyte chemotactic protein 1 (MCP-1), andplatelet-derived growth factor (PDGF) which are responsible for characterized symptoms including malaise, fever, and peripheral neutrophil leukocytosis. ^{[5] [6]}

• Genetic predisposition in alcoholism and developing alcohol -related liver injury:^[7]
  • There is a significant association between ADH2, ADH3, and ALDH2 alleles and the risk of alcoholism
    • The ADH2 and ADH3 alleles are associated with alcoholism in East Asians population
    • The ADH2 allele is associated with alcoholism in Caucasians
  • The association between genetic predisposition and development of alcoholic liver injury is unknown

Conditions associated with alcoholic liver disease include:^[2][8]

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

On microscopic histopathological analysis characteristic findings of Alcoholic Hepatitis include:

• Steatosis
  • Macrovesicular steatosis – the cytoplasm of hepatocytes is occupied by large lipid droplets that end up displacing the nucleus and other organelles peripherally
• Mallory body
  • A condition where pre-keratin filaments accumulate in hepatocytes. This sign is not limited to alcoholic liver disease.^[9]
• Ballooning degeneration
  • Hepatocytes in the setting of alcoholic change often swell up with excess fat, water and protein. Accompanied with ballooning, there is necrotic damage. The swelling blocks biliary ducts, leading to diffuse cholestasis.^[9]
• Inflammation
  • Neutrophilic invasion is triggered by the necrotic changes and cellular debris within the lobules.^[9]
• If chronic liver disease is also present:
  • Fibrosis
  • Cirrhosis

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