Week 3 P&I Flashcards
How much alcohol is a unit?
8g in the UK
What will the majority of alcohol abusers develop?
Steatosis
What can steatosis progress to?
Steatohepatitis
What percentage of alcohol abusers will develop cirrhosis?
10-20%
What is cirrhosis?
a combination of fibrosis and nodule development and regenerative tissue trying to regenerate in these nodules
What turns alcohol into acetaldehyde in the central pathway of alcohol metabolism?
ADH - Alcohol dehydrogenase
What turns acetaldehyde into acetate in the central pathway of alcohol metabolism?
ALDH - Acetaldehyde dehydrogenase
What are the two side pathways of alcohol metabolism?
- MEOS - microsomal ethanol oxidising system
2. Catalase
What enzyme is used in the MEOS pathway of alcohol metabolism?
CYP2E1
Where does the catalase pathway take place for alcohol metabolism?
Peroxisomes
What is a product of both side pathways of alcohol metabolism?
ROS - reactive oxygen species
What happens if there is excess of alcohol in the main metabolic pathway?
The central pathway can’t handle it by itself so it begins to go to the side pathways.
What are the consequences of acetaldehyde production?
- Binds to proteins and DNA –> prevents transcription of DNA
- Stimulates collagen production by Stellate cells
What are the consequences of acetate production?
Increased acetyl co-A promotes inflammation by histone acetylation –> prevents transcription
What are the consequences of increased NADH/NAD ratio?
Increased fatty acid synthesis; reduced fatty acid oxidation which promotes steatosis
What are the consequences of non-oxidative metabolism of alcohol?
Fatty acid ethyl ester production: promotes steatosis
What is the issue with more NADH going to the ETC in alcohol metabolism?
the ETC leaks electrons as well as producing ATP which produces superoxide ions and peroxidase and ultimately the most potent free radical the hydroxyl radical
What is the negative effect of the ETC leaking electrons?
The radicals created damage cell membranes and interrupt DNA transcription
What is the effect of TNF-a production?
Promotes apoptosis and necrosis, and activates stellate cells to produce collagen leading to fibrosis
What does increased intestinal permeability in chronic alcohol exposure cause?
Portal circulation endotoxemia
What cells are activated in Portal circulation endotoxemia?
Kupffer cells are constantly stimulated and produce more pro-inflammatory cytokines and ROS as well, which in turn promote liver injury
What is the intrinsic pathway of apoptosis initiated by?
Oxidative stress
What is the extrinsic pathway of apoptosis initiated by?
TNF-a
What do proteolytic caspases do?
Degrade cellular organelles
What is the main difference between apoptosis and necrosis?
Apoptosis = natural cell death Necrosis = traumatic cell death
what can vitamin deficiency in Chronic alcohol excess lead to?
impaired metobolism of methionine and reduction in glutathione
What are the consequences of disrupted methionine metabolism?
-Reduced SAM: SAH ratio
• Reduced transmethylation; impaired gene expression
• Increased Caspase-3/8 expression
o APOPTOSIS
• Increased TNF production (reduced IL-10)
o INFLAMMATION
• Reduced Cystathionine β-synthase activity
- Reduced Trans-sulfuration
• Reduced Glutathione production
o OXIDATIVE STRESS
What effect can obesity have in chronic excess of alcohol?
the enzyme that metabolises excess alcohol cytochrome P4502E1 is also induced so more POS
What are the histological findings in fatty liver?
Predominantly macrosteatosis in zone 2 and 3
What are the histological findings in Alcoholic hepatitis?
Swollen hepatocytes, giant mitochondria, steatosis, collagen in zone 3
What are the histological findings in Alcoholic cirrhosis?
Classically micronodular with or without alcoholic hepatitis
What is fibroscan - transient elastography used for?
To measure the stiffness/firmness of the liver
What are the essential features of ‘clinically relevant’ Alcoholic Hepatitis?
- recent excess alcohol (within 8 weeks)
- Bilirubin > 80mol/l (onset within 8 weeks)
- exclusion of other liver disease
- AST < 500 (AST: ALT ratio >1.5)
What are the main things that impact the progression of damage to the liver by alcohol?
Nutrition and obesity
