Alcoholic liver disease pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [2]

Overview

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.

Pathophysiology

Pathogenesis

  • 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]
  • 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]

Genetics

Associated Conditions

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

Gross Pathology

  • On gross pathology, characteristic findings of alcoholic liver disease include:[52]

Microscopic Pathology

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

  • 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.

References

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