Week 3 P&I

Question 1

How much alcohol is a unit?

Answer 1

8g in the UK

Question 2

What will the majority of alcohol abusers develop?

Answer 2

Steatosis

Question 3

What can steatosis progress to?

Answer 3

Steatohepatitis

Question 4

What percentage of alcohol abusers will develop cirrhosis?

Answer 4

10-20%

Question 5

What is cirrhosis?

Answer 5

a combination of fibrosis and nodule development and regenerative tissue trying to regenerate in these nodules

Question 6

What turns alcohol into acetaldehyde in the central pathway of alcohol metabolism?

Answer 6

ADH - Alcohol dehydrogenase

Question 7

What turns acetaldehyde into acetate in the central pathway of alcohol metabolism?

Answer 7

ALDH - Acetaldehyde dehydrogenase

Question 8

What are the two side pathways of alcohol metabolism?

Answer 8

1. MEOS - microsomal ethanol oxidising system

2. Catalase

Question 9

What enzyme is used in the MEOS pathway of alcohol metabolism?

Answer 9

CYP2E1

Question 10

Where does the catalase pathway take place for alcohol metabolism?

Answer 10

Peroxisomes

Question 11

What is a product of both side pathways of alcohol metabolism?

Answer 11

ROS - reactive oxygen species

Question 12

What happens if there is excess of alcohol in the main metabolic pathway?

Answer 12

The central pathway can’t handle it by itself so it begins to go to the side pathways.

Question 13

What are the consequences of acetaldehyde production?

Answer 13

• Binds to proteins and DNA –> prevents transcription of DNA
• Stimulates collagen production by Stellate cells

Question 14

What are the consequences of acetate production?

Answer 14

Increased acetyl co-A promotes inflammation by histone acetylation –> prevents transcription

Question 15

What are the consequences of increased NADH/NAD ratio?

Answer 15

Increased fatty acid synthesis; reduced fatty acid oxidation which promotes steatosis

Question 16

What are the consequences of non-oxidative metabolism of alcohol?

Answer 16

Fatty acid ethyl ester production: promotes steatosis

Question 17

What is the issue with more NADH going to the ETC in alcohol metabolism?

Answer 17

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

Question 18

What is the negative effect of the ETC leaking electrons?

Answer 18

The radicals created damage cell membranes and interrupt DNA transcription

Question 19

What is the effect of TNF-a production?

Answer 19

Promotes apoptosis and necrosis, and activates stellate cells to produce collagen leading to fibrosis

Question 20

What does increased intestinal permeability in chronic alcohol exposure cause?

Answer 20

Portal circulation endotoxemia

Question 21

What cells are activated in Portal circulation endotoxemia?

Answer 21

Kupffer cells are constantly stimulated and produce more pro-inflammatory cytokines and ROS as well, which in turn promote liver injury

Question 22

What is the intrinsic pathway of apoptosis initiated by?

Answer 22

Oxidative stress

Question 23

What is the extrinsic pathway of apoptosis initiated by?

Answer 23

TNF-a

Question 24

What do proteolytic caspases do?

Answer 24

Degrade cellular organelles

Question 25

What is the main difference between apoptosis and necrosis?

Answer 25

``` Apoptosis = natural cell death Necrosis = traumatic cell death ```

Question 26

what can vitamin deficiency in Chronic alcohol excess lead to?

Answer 26

impaired metobolism of methionine and reduction in glutathione

Question 27

What are the consequences of disrupted methionine metabolism?

Answer 27

-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

Question 28

What effect can obesity have in chronic excess of alcohol?

Answer 28

the enzyme that metabolises excess alcohol cytochrome P4502E1 is also induced so more POS

Question 29

What are the histological findings in fatty liver?

Answer 29

Predominantly macrosteatosis in zone 2 and 3

Question 30

What are the histological findings in Alcoholic hepatitis?

Answer 30

Swollen hepatocytes, giant mitochondria, steatosis, collagen in zone 3

Question 31

What are the histological findings in Alcoholic cirrhosis?

Answer 31

Classically micronodular with or without alcoholic hepatitis

Question 32

What is fibroscan - transient elastography used for?

Answer 32

To measure the stiffness/firmness of the liver

Question 33

What are the essential features of 'clinically relevant’ Alcoholic Hepatitis?

Answer 33

- recent excess alcohol (within 8 weeks) - Bilirubin > 80mol/l (onset within 8 weeks) - exclusion of other liver disease - AST < 500 (AST: ALT ratio >1.5)

Question 34

What are the main things that impact the progression of damage to the liver by alcohol?

Answer 34

Nutrition and obesity