Alcohol & Hepatopathology

Question 1

Where is alcohol normally metabolised?

Answer 1

Hepatocytes

Question 2

Describe the preferred mechanism of alcohol metabolism?

Answer 2

In the cytosol, alcohol is converted to acetyl aldehyde by Alcohol Dehydrogenase. This causes NADH production from NAD.
In the mitochondria, acetyl aldehyde is converted to Acetate by Acetylaldehyde Dehydrogenase.
Acetate can then be converted to CO2, or to Acetyle-CoA which enters the Krebs cycle.

Question 3

What is the toxic product of alcohol metabolism?

Answer 3

Acetyl-aldehyde.

Question 4

What happens when there is an excess of alcohol and this main metabolism method is flooded?

Answer 4

There are 2 overflow pathways.

1. The microsomal Ethanol Oxidising System: Where alcohol is converted to Acetyl Aldehyde via CYP2E1. This also converts NADPH to NADP, and produces ROS.
2. Alcohol is converted to acetyl aldehyde in the perioxisome by Catalase. This also produces ROS.

Question 5

What are the concequences of acetyl aldehyde production?

Answer 5

Binds to membrane proteins and becomes immunogenic.

Also stimulates stellate cells to produce collagen.

Question 6

What are the concequnces of Acetate production?

Answer 6

Acetate goes on to make acetyl-coA which promotes inflammation by histone acetylation, which causes transcription of proinflammatory cytokines.
Can also go on to make fatty acids causing steatosis.

Question 7

What are the consequences of increased NADH/NAD production?

Answer 7

Increased fatty acid synthesis and reduced fatty acid oxidation which leads to steatosis.

Question 8

Describe the consequences of ROS production?

Answer 8

Produces hydrogen peroxide and superoxide ions.
This activates transcription factors such as NFkB which causes pro-inflammatory cytokine production, such as TNF-alpha. NFkB also causes IL-8 production and neurtrophil activation.
TNF-alpha promotes apoptosis and necrosis, and also activates stellate cells to produce collagen.

Question 9

Describe the intrinsic apoptosis pathway?

Answer 9

Initiated by oxidative stress and free radicals.
Causes leakage of pro-apoptotic factrors from the mitochondria, such as Cytochrome C. These activate Capsases which cause cell degredation.

Question 10

Describe the extrinsic apoptotic pathway?

Answer 10

Initiated by TNF-alpha, binding to TNF receptors causing Capsase activity via FADD and TRADD proteins.

Question 11

What happens when capsases are activated?

Answer 11

Proteolytic enzymes degrade cellular organelles and cellular components are broken down into vesicles called apoptotic bodies.

Question 12

What is the difference between apoptosis and necrosis?

Answer 12

Apoptosis - natural cell death stimulated by cell signals. Produces cell fragments that can send signals to facilitate apoptosis.

Necrosis - traumatic cell death that is stimulated by external factors and cant send signals so dead tissue and cell debris can build up.

Question 13

How does obesity cause problems with alcohol consumption?

Answer 13

Alcohol induces lipidystrophy causing an increase in central fat.
CYP2E1 is induced by free fatty acids
Obesity is a proinflammatory state, so there is an increase in inflammatory mediators in response to endotoxaemia.

Question 14

What is Fibroscan?

Answer 14

Measures the stiffness of the liver. Sends a sound pulse through liver and identifies the speed of return.
If hard and fibrotic - there is a faster return.

Question 15

Describe LFT’s found in alcoholic hepatitis?

Answer 15

Bilirubin >80

AST:ALT >1.5

Question 16

What is the Childs Turcotte Pugh Score?

Answer 16

Used to assess the prognosis of liver disease.

Based of encephalopathy, ascites. bilirubin, albumin, prothrombin time.

Question 17

Describe each grade of the Childs Pugh Score?

Answer 17

Grade A - mild, compensated liver disease.
B - moderate
C - Severe and uncompensated.

Question 18

How does hepato-renal syndrome occur?

Answer 18

Cirrhosis causes portal hypertension, which causes splanchnic vasodilation (more blood to intenstine so more blood to portal system), causing a decrease in effective circulating volume. This activates the RAAS causing constriction of the renal vessels hepato-renal syndrome.

Question 19

How does acites occur?

Answer 19

Cirrhosis causes portal hypertension, which causes splanchnic vasodilation, causing a decrease in effective circulating volume. This activates the RAAS causing sodium retention, aldosterone acts to till increase sodium and water, leading to ascites.

Question 20

What is a unit of alcohol?

Answer 20

8g of ethanol e.g. a 1/2 pint, 80ml of wine, 25ml of spirit.

Question 21

What is the advised alcohol limit?

Answer 21

14 units a week for both males and females, with 2-3 days alcohol free.

Question 22

What is the drink driving limit?

Answer 22

50mg of alcohol per 100ml of blood

22ug of alcohol per 100ml of breath.

Question 23

Why is alcohol not advised in pregnancy?

Answer 23

As alcohol can pass through the placenta from mothers blood to babies blood as the placenta allows free entry of ethanol and toxic metabolites such as acetyl aldehyde to the fetal compartment.
The fetal NS is sensitive to ethanol toxicity and can impact on proliferation, differentiation, neuronal migration and axonal growth. This impairs white matter development.
The liver is incapable of detoxifying alcohol as ADH and ALDH enyzmes are no expressed, so the fetus is exposed to ethanol for a longer time.

Question 24

How is fetal alcohol syndrome diagnosed?

Answer 24

Growth deficiency: below the 10th centile. Often have low birth weight.
FAS Facial features: Smooth philtrum, thin vermillion, small palpebral fissures, low nasal bridge, skin folds at corner of eye.
CNS damage: Structural or functional impairment. Learning difficulties, cognitive abnormalities, attention problems, social skills impairment, visual or hearing impairment.
Pre-natal Alcohol Exposure

Question 25

What is binge drinking?

Answer 25

Having more than 6 units at one time. Usually a period of abstinence in between.