Week 5

Question 1

predominant pathway to acetaldehyde

- oxidizing agent

Answer 1

• conversion of ethanol to acetaldehyde via ADH

- NAD+ –> NADH

Question 2

CYP2E1

• what is it?
• relation to OH
• importance

Answer 2

• part of the cytochrome P450 system
• enzyme will be increased when drinking
• since enzyme is increased then it will be the predominant pathway used to make acetaldehyde

Question 3

alcohol-induced steatosis

• what causes it?
• NAD?

Answer 3

• when you have a lot of conversion of ethanol, you get a build up of ADH, and ratio will inhibit beta-oxidation of fatty acids.
• Also, NAD+ is required for beta oxidation of fatty acids but since it being used to convert PH to acetalaldehyde then it causes for the fat coming in to be stored instead of broken down and used for energy

Question 4

Why are some individuals and populations more susceptible to toxic effects of alcohol metabolism?

Answer 4

They have less alcohol dehydrogenase

Question 5

ALDH mutation

Answer 5

• resulting in deficient ALDH function.
• Asian
• lethargy, fever, or hyperventilation, but very classically their skin flushes

Question 6

Steatosis

Answer 6

• lipid accumulation in the hepatocytes causing for the nucleus to be pushed to the side
• reversible is insult is removed
• can be asymptomatic

Question 7

Steatohepatitis

Answer 7

• hepatocyte swelling and necrosis going on, and that’s when you get the Mallory-Denk bodies coming in and you get an inflammatory reaction, so you also have neutrophils coming in
• need to see necrosis in order to dx this
• reversible

Question 8

Steatofibrosis

Answer 8

• fibrosis done by the stellate cells
• Pericellular
• reversible

Question 9

mechanisms of progression from alcoholic steatosis to steatohepatitis

Answer 9

• Direct: Alcohol facilitates the release of endotoxin from the gut, overwhelming the protective mechanisms and inciting inflammatory response
• Indirect: 1- acetaldehyde, is toxic and can induce lipid peroxidation, free radical formation, and depletes glutathione; 2- Induction of the cytochrome P450 potentiates effects of other toxins allowing for toxic metabolites to accumulate faster; enhances lipid peroxidation, increase production of ROS leading to oxidative injury and mito disruption/apoptosis

Question 10

hepcidin

• function
• priteins facilitating synthesis

Answer 10

• Decreases the amount of iron absorbed by binding to ferroportin on basolateral side of enterocyte
• HFE, HJV, TFR@

Question 11

How can the secondary pathway lead to toxic liver injury?

Answer 11

• make too much NAPQ which is toxic and once all the glutathions are used up then body is exposed to toxicity

Question 12

antidote to acetaminophen toxicity, and what is its mechanism of action?

Answer 12

• N-acetylcysteine: restores glutathione
• This antidote has a narrow window: once the toxic metabolites build up, it’s too late. You can give them all of the glutathione in the world, but the toxic metabolites have already been created
• antidote is given via a nebulizer

Question 13

mechanisms of liver toxicity in iron overload

Answer 13

• lipid peroxidation via iron catalyzed free radical reactions
• stimulation of collagen formation by activation of hepatic stelate cells
• interaction of ROS and iron with DNA leading to lethal cell injury and pre-disposition to HCC

Question 14

Can iron tox be reversible

Answer 14

• only in cells that are not fatally injured and there has been removal of excess iron
• also the use of therapy to promote recovery of tissue function is helpful