HTHSCI 1DT3 Lecture Notes - Lecture 15: Ascites, Peripheral Edema, Osteoporosis
23 Jun 2018
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Pathogenesis of ALD - antoinedes
Alcohol is metabolised by three main pathways:
1) alcohol dehydrogenase (cytosol)
2) catalase (peroxisomes)
3) MEOS (microsomal ethanol oxidising system) – CYP2E1, which is upregulated in chronic
alcohol ingestion and is involved in ALD pathogenesis by the release of ROS (ER)
- These pathways convert alcohol acetaldehyde which is converted by aldehyde dehyrdgenase
(ALDH) acetate CO2 + H20
Direct mechanism of liver damage
- Acetaldehyde is hepatotoxic; it generates ROS
- Also, action of ADH causes NADPH production, which promoted steatosis by increasing production
of FAs and reducing their oxidation
- Injury is in the perivenous area; reasons for this localisation may include:
1) lack of oxygenation
2) ethanol metabolism by ADH
3) ethanol metabolism by ALDH
4) MEOS
5) Relative deficiency of antioxidant levels
Immune-mediated mechanisms of liver damage
1) gut-liver axis = role of endotoxin / oxidative stress
Earliest event in rodent model of ETOH is an increase in gut permeability followed by an
increase in LPS (endotoxin) leading to steatosis
Translocation of LPS portal vein activation of resident macrophages of the reticulo-
endothelial system in liver via TLR4 TNF-alpha + ROS + fibrosis + cirrhosis
TLR acts through Myd88 to activate NfkappaB generation of TNF-alpha
TRIF activate NfkappaB & activate IRF3 generation of IFN-beta
2) innate immune axis = comprises Kupffer cells, neutrophils, lymphocytes
neutrophils:
predominate in the cellular infiltrate on biopsy
levels correlate with disease severity
Neutrophils (Nφ) recruitment and activation occurs through TNF-a mediated chemokine
production (e.g. MCP-1)
Neutrophil chemotaxis to liver sinusoids induced by HMGB-2, Gro-alpha, IL-8
Neutrophil extravasation into liver parenchyma controlled by CXC chemokines and other
mediators release by dying hepatocytes
Following Kupffer cell (KC) and macrophage (mφ) activation by a noxious stimulus
hepatocyte death is induced by both direct and indirect mechanisms.
Hepatocyte apoptosis can occur through the direct interaction of TNF-a and Fas ligand (FasL)
with their respective ligands on hepatocytes.
Indirect mechanisms of hepatocyte death occur through TNF-a-induced activation of liver
sinusoidal endothelial cell (LSEC). Platelet activation, sinusoidal fibrin deposition, reduced
fibrinolysis due to increased concentrations of plasminogen activator inhibitor (PAI-1) and
widening of the LSEC fenestrations lead to hepatic microvascular dysfunction/ischaemia and
hepatocyte death.
Increased expression of LSEC adhesion molecules and chemoattractant mediator production
(IL-8, platelet activating factor) promotes influx of further immune effector cells
3) Role of inflammatory cytokines (TNF-alpha)
CNS: encephalopathy, anorexia, fever
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Document Summary
Alcohol is metabolised by three main pathways: Pathogenesis of ald - antoinedes: alcohol dehydrogenase (cytosol, catalase (peroxisomes, meos (microsomal ethanol oxidising system) cyp2e1, which is upregulated in chronic alcohol ingestion and is involved in ald pathogenesis by the release of ros (er) These pathways convert alcohol acetaldehyde which is converted by aldehyde dehyrdgenase (aldh) acetate co2 + h20. Also, action of adh causes nadph production, which promoted steatosis by increasing production of fas and reducing their oxidation. Injury is in the perivenous area; reasons for this localisation may include: lack of oxygenation. 1: ethanol metabolism by adh, ethanol metabolism by aldh, meos, relative deficiency of antioxidant levels. Immune-mediated mechanisms of liver damage: gut-liver axis = role of endotoxin / oxidative stress. Earliest event in rodent model of etoh is an increase in gut permeability followed by an increase in lps (endotoxin) leading to steatosis.
