Alcohol Metabolism, alcohol liver disease and alcoholism Flashcards
What is haematemesis?
- vomiting blood
What is melaena?
- black tarry stool
- digested blood from upper GIT
What is 1 unit of alcohol equal to?
- 100mls glass of wine
What are the goverment recommendations for how much alcohol men and women should consume?
- no more that 14 Units on a regular basis
What age category is alcohol consumption the highest, and do men or women consume more?
- 55-64 years old
- men = 38%
- women = 19%
What are the 4 main alcohol releated reasons why patients are admitted to hospital?
1 - alcohol Withdrawal seizures
2 - alcoholic hepatitis
3 - decompensated cirrhosis
4 - alcoholic pancreatitis
When we talk about alcohol, what do we generally refer to?
- ethanol
Can ethanol, which is alcohol be stored in the body?
- no
- it must be metabolised
Is ethanol (alcohol) water soluble?
- yes completely mixable with water
- if water is high in tissue so to is alcohol
Is ethanol (alcohol) able to pass through biological membranes?
- yes
- perfuses into tissue from blood and is dependent on H2O content
Of all the ethanol (alcohol) that we consume, how much is metabolised?
- 90%
- 10% lost in our breathe, urine or sweat
Where is alcohol generally metabolised?
- in the liver
Once ethanol (alcohol) reaches the liver, what enzymes is responsible for converting it to Acetaldehyde, and where in the hepatocytes does this occur (cytosol or mitochondria)?
- alcohol dehydrogenase (ADH)
- occurs in cytosol
Once ethanol (alcohol) reaches the liver, alcohol dehydrogenase reduces ethanol into acetaldehyde in the cytosol of the hepatocytes, which is a reversible reaction (acetaldehyde can be converted back into ethanol). What happens to ethanol to become acetaldehyde?
- 2 electrons and 2 H+ are removed from ethanol
- electrons and H+ are added to the coenzymes NAD+ forming NADH and H+
Once ethanol (alcohol) reaches the liver, alcohol dehydrogenase (reversible reaction) reduces ethanol into acetaldehyde in the cytosol of the hepatocytes, removing 2 H+ and 2 electrons and transfering them to the coenzymes NAD+, which becomes NADH. What is the next step of ethanol (alcohol) metabolism in the liver?
- acetaldehyde is converted into into acetic acid
Once ethanol (alcohol) reaches the liver, alcohol dehydrogenase (reversible reaction) reduces ethanol into acetaldehyde in the cytosol of the hepatocytes, removing 2 H+ and 2 electrons and transfering them to the coenzymes NAD+, which becomes NADH. Acetaldehyde is then converted into into acetic acid. What enzyme is responsible for this and where in the hepatocytes does this occur?
- aldehyde dehydrogenase (ALDH) (this is a reversible reaction)
- occurs in mitochondria
Aldehyde dehydrogenase (ALDH) is an enzyme that convertes acetaldehyde into acetate, which is a reversible reaction. What happens to acetaldehyde during this reaction?
- reduction of NAD+ to NADH
- 2 H+ and 2 electrons are removed from acetaldehyde
- electrons and H+ are added to NAD+ forming NADH + H+
Once acetate has been formed by the conversion of ethanol to acetaldehyde, what happes to the acetate?
- majority leaves liver and travels to peripheries
- combined with coenzyme-A
- coenzyme-A + acetate = Acetyl CoA
Once acetate has been formed by the conversion of ethanol to acetaldehyde, the majority leaves liver and travels to peripheries. Here it is combined with coenzyme-A forming Acetyl CoA. What can then happen to Acetyl CoA?
- produce cholesterol
- fatty acids
- ketone bodies
- enter citric acid cycle and form CO2
Most enzymes have a lock and key approach, meaning they are very specific to certain reactions. However, alcohol dehydrogenase has a broad specificity. Where is it found and what 3 compounds is it able to act on?
- ethanol, methanol, propanol
- located in the cytosol
What are isoforms?
- proteins that are similiar in structure and function and likley come from the same gene
- BUT some isoforms may have specific roles in the body
Why are alcohol dehydrogenase (ADH) isoforms important in the liver?
- some ADH have higher affinity for ethanol
- some may metabolise alcohol quickly and others may not
- explains why some people are drunk more easily
Methanol (CH3OH), a smaller molecule than ethanol is another substrate for alcohol dehydrogenase. What is methanol converted to in the liver?
- formaldehyde which is very toxic
- methanol is oxidised from CH3OH to CH2O
Methanol (CH3OH), a smaller molecule than ethanol is another substrate for alcohol dehydrogenase. Methanol is converted to formaldehyde, which is very toxic via oxidation using alcohol dehydrogenase from CH3OH to CH2O. The liver can then convert formaldehyde into another compound, what enzyme is responsible for this second conversion?
- aldehyde dehydrogenase
- formaldehyde converted into formic acid, which is also toxic
Methanol (CH3OH), a smaller molecule than ethanol is converted into formaldehyde, and then formic acid. Both formic acid and formaldehyde are toxic to the body. Once formic has been formed in the liver it can enter the blood stream and is especially toxic towards what cells and tissue?
- consumption of methanol can lead to blindness
- neuronal tissue causing blindness
- able to inhibt complex 4 of electron transport chain, so no water formation and reduced ATP
Due to how dangerous formic acid is, how is the body able to remove this?
- folate can be used to oxidise it
- CO2 and H2O are then formed
If a patient is suspected of consuming methanol, which can be dangerous, what could you do to reduce the risks associated with methanol?
- consume ethanol
- ethanol outcompetes methanol for alcohol dehydrogenase
- methanol can therefore not be metabolised
What is Ethylene glycol (Antifreeze) Poisoning?
- poisioning caused by drinking anti-free
What is Ethylene glycol (Antifreeze) Poisoning is dangerous and can cause metabolic acidosis. How is Ethylene glycol metabolised in the liver?
- oxidised by alcohol dehydrogenase into glycoaldehyde
- glycoaldehyde is then oxidised by aldehyde dehydrogenase
into glycolic acid
Glycolic acid is the metabolite of ethylene glycol (Antifreeze) can cause metabolic acidosis. How does this occur?
- can be oxidised into glyoxylic acid by lactate dehydrogenase
- can then form oxalic acid which is able to form crystals in the kidneys
What is the main compound that is created by ethanol metabolism?
- NADH
- increased NADH offsets the NADH/NAD+ ratio
- can overload the electron transport chain
The main compound that is created by ethanol metabolism is NADH. Increased NADH offsets the NADH/NAD+ ratio and overload the electron transport chain (ETC). What can happen if the ETC is overun due to a low NAD+/NADH ratio?
- inhibition of oxidative and catabolic processes, such as glycolysis and oxidative respiration
- acceleration of synthesis pathways, such as fatty acid and glcogen synthesis
The main compound that is created by ethanol metabolism is NADH. Increased NADH offsets the NADH/NAD+ ratio and overload the electron transport chain (ETC). The catabolic and oxidative pathways are shifted to reductive synthetic processes. What are the 5 main catabolic/oxidative pathways that are inhibited?
- glycolysis
- citric acid cyle (uses acetyl-CoA)
- pyruvate dehydrogenase (converts pyruvate into acetyl-CoA)
- fatty acid oxidation (fat breakdown)
- gluconeogenesis
The main compound that is created by ethanol metabolism is NADH. Increased NADH offsets the NADH/NAD+ ratio and overload the electron transport chain (ETC). The catabolic and oxidative pathways are shifted to reductive synthetic processes. If the ETC has a lot of NADH it thinks that it has lots of energy and therefore slows down what cycle that feeds into the ETC?
- citric acid cycle is slowed down
- acetyl-CoA (formed at the end of glycolysis) then builds up
- lots of acetyl-CoA tells hepatocytes to synthesis lipids and triglycerides
What 2 molecules in excess in the liver, related to alcohol consumption are responsible for turning on lipid synthesis?
- NADH
- acetyl-CoA
In addition to triggering lipid synthesis, the formation of lots of acetyl-CoA due to an inhibition of the citric acid cycle can lead to the formation of what? This molecule is normally formed and released from the liver during starvation states.
- ketones
- causes ketosis (high ketons in the blood)
NADH is formed during alcohol metabolism. This can offset the NAD+/NADH ratio in the electron transport chain (ETC). Due to a low NAD+/NADH ratio the ETC thinks we have an abundance of energy and inhibits the cirtic acid cycle. Inhibition of the citric acid cycle results in a build up of the end product of glycolysis, acetyl- CoA. The build up of acetyl-CoA triggers lipid synthesis which produce fat. What then happens to this fat?
- stored in the liver as triglycerides and lipid droplets
One method of using NADH is to convert pyruvate into lactate. If we are converting pyruvate into lacate, what can this cause?
- lactate is released from the liver into the blood and could cause lactic acidosis
- glycolysis is inhibited by high acetyl-CoA so lactate cannot be recycled
- converting pyruvate into lactate means no substrate for gluconeogenesis
One method of using NADH is to convert pyruvate into lactate. The lacate that is formed from pyruvate through the recylcing of excessive NADH is released into the blood. This causes pyruvate levels in the liver, that can be used during gluconeogenesis to drop. Gluconeogenesis is crucial for mainting blood glucose levels. If gluconeogenesis is reduced what can be seen in patients?
- hypoglycaemia
What can alcohol do to mean corpulsar volume of RBCs?
- increase
Patients consuming high levels of alcohol may have raised antibodies, which antibody can be detected in blood and indicate alcoholic liver problems?
- IgA
When looking at the cause of a patients abnormal liver function tests, what would we expect to see in the raised in a patient with suspected alcoholic liver disease?
- really high AST levels
- larger increase in AST over ALD
- AST > ALT
What are 2 of the most specific clinical presentations of patients with alcoholics liver disease in relation to the hands and face?
- dupuytren’s contractures
- parotid swelling
What are the 4 stages of liver damage that can lead to liver cirrhosis?
1 - liver steatosis
2 - liver steatohepatitis
3 - liver fibrosis
4 - liver cirrhosis
Where does the portal mesenteric system drain into?
- the liver
The liver can be viewed as the washing machine of the body. It is able to:
- wash and drain away any toxins
- pumps out clean blood off to heaptic vein and the superior vena cava
But what can happen if the liver becomes damaged and scarred, meaning blood builds up inside or in the veins leading into the vein?
- hepatic portal hypertension
What can hepatic portal hypertension do to the spleen?
- blood backs up the splenic artery and platelets removed, meaning platelet count will be low
- splenomegaly as a result of high blood in splenic artery
What can hepatic portal hypertension do to the oesophagus and stomach?
- increased pressure in veins supplying them
- varices can form (dilated, swollen veins)
Hepatic portal hypertension cause cause gastric and oesophageal varices. What are 2 common signs a patient has gastric and oesophageal varices?
- haematemesis (vomitting blood)
- melaena (dugested blood in stool)
What are the 2 main presentations of why patients are admitted to hospital?
- alcoholic hepatitis
- decompensated cirrhosis
What is alcoholic hepatitis?
- acute inflammation of hepatocytes due to alcohol
- patients present with jaundice
- patents dont have cirrhosis but will have steatohepatitis
What is decompensated cirrhosis due to ALD?
- patients will have cirrhosis but liver is functioning still
- decompensated cirrhosis means liver is begining to fail or drop of a cliff, function wise
- patients can have encephalopathy, variceal bleeding or ascites or all of them
What are ascites?
- fluid collects in spaces within your abdomen
In 30-40% of patients who consume over 14 units of alchol per day on a regular basis are likley to develop steatohepatitis. This can cause what in hepatocytes?
- hepatic ballooning
- Mallory-Denk bodies (clumps of cytoskelten components called intermediate components)
- immune cell infilitration and fibrosis
In 30-40% of patients who consume over 14 units of alchol per day on a regular basis are likley to develop steatohepatitis. In addition to hepatic ballooning, this can cause infiltration of immune cells, which can lead to what?
- inflammation
What can inflammation in hepatocytes do to Kupffer cells (macrophages of the liver)?
- switch them to become inflammatory
- turn to M1 cells and consume damaged cells
- release cytokines and produce reactive oxygen species
Inflammation can lead to damage of the cells of the liver, which can then lead to what?
- chronic inflammation and induces apoptosis
- repairs liver with fibrotic scar tissue
- reduces parenchyme tissue in the liver
Inflammation can lead to damage of the cells of the liver, which can then lead to chronic inflammation and apoptosis induction. The cells are repaired with fibrotic scar tissue, but this can reduce parenchyme tissue in the liver. This can lead to compensated and decompensated phase of liver damage, what is the difference between these?
- compensated phase = part of the liver remains undamaged and compensates for damaged regions
- decompensated phase = scar tissue fully envelopes the organ, causing portal hypertension and / or liver failure
What are hepatic stellate cells?
- liver cells that provide the liver with an ability to respond to injury and heal certain types of damage
Hepatic stellate cells generally provide the liver with an ability to respond to injury and heal certain types of damage. However, in chronic liver inflammation, how do they contribute to fibroisis?
- secrete pro-inflamatory cells
- secrete collagen and lay down scar tissue causing cirrhosis
What does CAGE stand for when taking a patients medical history?
- C = Cut down (have you felt the need to Cut down your drinking?)
- A = Annoying (have people Annoyed you by criticising your drinking?)
- G = Guilty (have you ever felt Guilty about you drinking?)
- E = Eye opener (have you drank in the morning to steadu your nerves, acts as an Eye opener)
The CAGE mnemonic stands for:
stand for when taking a patients medical history?
- C = have you felt the need to Cut down your drinking?
- A = have people Annoyed you by criticising your drinking?
- G = have you ever felt Guilty about you drinking?
- E = have you drank in the morning to steadu your nerves, acts as an Eye opener
What score is indicitive of alcolism?
- a score of 4 indicates alcoholism
- a score of 2 or 3 is highly suspicious
Following an abrupt withdrawal of alcohol consumtion, how soon can alcohol withdrawal occur?
- within 6-72 hours
Following an abrupt withdrawal of alcohol consumtion, alcohol withdrawal can occur within 6-72 hours, what is the mortality rate of alcohol withdrawal?
- 15%
Following an abrupt withdrawal of alcohol consumtion, alcohol withdrawal can occur within 6-72 hours, and has a mortality rate of 15%. What does the mnemonic HITS mean when looking to see if a patient has alcohol withdrawal?
- hallucinations
- insomnia and increased vital signs
- tremens delirium
- shakes, sweats seizures
Following an abrupt withdrawal of alcohol consumtion, alcohol withdrawal can occur within 6-72 hours, and has a mortality rate of 15%. If a patient is admittied to hospital with alcohol withdrawal, the clinical team can use the CIWA and SADQ scores for what?
- CIWA score – Clinical Institute Withdrawal Assessment
- SADQ score – Severity of Alcohol Dependence
- determines drug dosage, timing and frequency
What causes Wernicke Korsakoff syndrome?
- B1 (thiamine) deficiency
Wernicke Korsakoff syndrome is dividied into the reversible Wernicke Encephalopathy and Korsakoff syndrome. What is Wernicke Encephalopathy?
- neurological symptoms
- biochemical lesions form in CNS due to B1 (thiamine) deficiency
- this is reversible
Wernicke Korsakoff syndrome is dividied into the reversible Wernicke Encephalopathy and Korsakoff syndrome. Wernicke Encephalopathy presents with neurological symptoms due to biochemical lesions form in CNS due to B1 (thiamine) deficiency, but the condition is reversible. How are these patients treated?
- provide thiamine intravenously for 48 hours
- oral thiamine. follows
- do not give glucose before.
Wernicke Korsakoff syndrome is dividied into the reversible Wernicke Encephalopathy and Korsakoff syndrome. Wernicke Encephalopathy presents with neurological symptoms due to biochemical lesions form in CNS due to B1 (thiamine) deficiency, but the condition is reversible. However, if left untreated it can lead to Korsakoff syndrome, what is this?
- non-progressive type of dementia/psychosis
- non-reversible
Thamine phosphotase, the metabilically active part of thiamine is an important co-enzyme that is important for glucose metabolism, such as pyruvate dehydrogenase, which convert pyruvate into acetyl-CoA by adding CoA onto pyruvate. How would B1 (thiamine) deficiency affect glucose metabolism?
- pyruvate dehydrogenase activity would be low
- build up of pyruvate in cell and reducion of NADH, FADH for elcron transport chain and ATP generation
What are the 3 ways alcohol abuse can lead to Wernicke-Korsakoff syndrome?
1 - blocking thaimine phosphorylation
2 - ethanol inhibits thiamine absorbtion
3 - fatty liver/cirrhosis interferes with thiamine storage
