Session 1 - Alcohol metabolism Flashcards
What percentage of alcohol is passively excreted rather than actively metabolised?
10%
Excreted in urine and on the breath
Describe the main pathway for alcohol metabolism
What happens to the end product in this pathway?
(In liver)
- Alcohol is oxidised to acetaldehyde by alcohol dehydrogenase (reducing NAD+ to NADH)
- Acetaldehyde oxidised to acetate by aldehyde dehydrogenase
(reducing NAD+ to NADH)
Acetate is converted to Acetyl CoA which enters general metabolism (Citric Acid Cycle)
Acetaldehyde has what effect on liver cells?
How is this usually controlled?
Very hepatotoxic
Toxicity is limited because it is removed very fast by aldehyde dehydrogenase (high affinity; low Km)
What is the Km?
Amount of substrate needed to achieve 1/2 of the Vmax
A low Km indicates high affinity
What other liver enzyme can metabolise small amounts of alcohol?
(Minor pathway)
How else can alcohol be metabolised?
- CYP2E1
(a Cytochrome P450) - catalase in the brain
In alcoholism, which enzyme’s capacity is saturated?
Aldehyde dehydrogenase so acetaldehyde accumulates
How can alcoholism exacerbate gout?
- Excess alcohol metabolism reduces levels of NAD+ in the body
- Can’t convert lactate back to pyruvate bc this requires NAD+ as an oxidising agent
- Lactic acidosis/ high lactate reduces excretion of uric acid by the kidneys
- Gout attack
Why may an alcoholic be hypoglycaemic?
No gluconeogenesis because low levels of NAD+ prevent glycerol metabolism and conversion of lactate back to pyruvate
(low levels of NAD+ due bc it’s used in alcohol oxidisation)
How do you treat gout?
Allopurinol
(purine analogue) which inhibits xanthine oxidase; enzyme that catalyses conversion of xanthine to uric acid
Where does uric acid come from?
What accumulates in the joints in gout?
What causes the inflammation?
Metabolism of purines
crystals of monosodium urate
- neutrophils try to phagocytose the crystals but are killed doing so
- neutrophil death releases lysosomal enzymes into the surrounding tissue.
- This causes inflammation and local cell lysis
Why can alcoholics look yellow?
- An accumulation of acetaldehyde (hepatotoxic) reduces liver function.
- Reduced conjugation of bilirubin (thus excretion) leading to hyperbilirubinaemia and jaundice
Why do alcoholics have a fatty liver?
More lipid synthesis and less removal
- Liver is damaged due to accumulation of acetaldehyde (hepatotoxic)
- Less protein synthesis occurs
- Less lipoproteins to transport lipids out of the liver (main site of lipogenesis)
- Lipid accumulates
Exacerbated due to high levels of acetyl CoA increasing the synthesis of fatty acids
- Fatty acids converted to triacylglycerols in the liver
The livers of alcoholics synthesise less protein.
Name 3 important proteins which are affected and the pathological impact
- less lipoprotein so lipids accumulate in the liver (fatty liver)
- less albumin which causes tissue oedema
- less clotting factors increases the time taken to clot
Why does liver damage increase the levels of ammonia and glutamine in the blood?
Usually the liver converts them to urea
Why do we test for these enzymes in the blood?
- Transaminases
- Gamma glutamyl transpeptidase
Indicate liver damage (LFT’s)
Leak out of damaged hepatocytes (with leaky membranes)
High levels of acetyl CoA are converted to what two things?
Fatty acids
Ketone bodies
How can you detect ketoacidosis?
fruity smelling breath
What effect does alcohol have on the GI tract?
Damages the gut epithelium leading to diarrhoea, loss of appetite and impaired absorption of nutrients like Vitamin K, folic acid and thiamine (B1 vitamin)
Impaired absorption of folic acid can cause what hematological effect?
Megaloblastic anaemia because you need folic acid to make red blood cells
Which vitamin deficiency causes neurological symptoms?
What syndrome can this cause?
Thiamine deficiency
Wernicke-Korsakoff syndrome; mental confusion and unsteady gait
Why is Wernicke-Korsakoff syndrome common in chronic alcoholism?
Alcohol damages the epithelial lining of the GI tract causing impaired absorption leading to thiamine deficiency which causes WKS
How does alcoholism cause diabetes?
Heavy consumption causes chronic pancreatitis (inflammation of the pancreas) which damages the pancreatic cells; including the beta cells of the islets of langerhans which secrete insulin
Symptoms of pancreatitis? (Inflammation of the pancreas)
Weight loss due to malabsorption because the pancreatic (digestive) enzymes are not released into the duodenum
Pain in the upper abdomen radiating to the back
Which drug can you give for alcohol dependance?
How does it work?
Disulfiram
Inhibits aldehyde dehydrogenase so when the patient drinks alcohol, acetaldehyde accumulates; feels like a hangover, nausea
How do mitochondria produce superoxide radicals?
In oxidative phosphorylation, a small percentage (>2%) of electrons do not reach the end of the electron transport chain; they prematurely reduce oxygen to form superoxide radicals
