Alcohol related liver disease Flashcards
What is the main metabolism pathway for alcohol?
Ethanol => acetaldehyde +NADH by alcohol dehydrogenase => acetate + NADH by aldehyde dehydrogenase and then acetate is excreted
What is the rate limiting step for the main metabolic pathway of ethanol?
NAD to NADH - ability of liver to re-oxidise NADH
What are the other 2 pathways to metabolise ethanol?
SER
ethanol=> acetylaldehyde by O2+ NADPH + cyp2e1 + h20 + NADP
Ethanol => acetylaldehyde by peroxisomal catalase producing water as well
What is the problem with a mutant allele of aldehyde dehydrogenase?
inability to breakdown acetylaldehyde => homoxygotes suffer high circualting acetaldehyde and flushing
40% orientals = autosomal dominant mutant allele
heterozygotes develop liver disease at lower levels of alcohol consumption
What is the most toxic substance in the alcohol metabolism pathway?
acetylaldehyde = approx. 40 times more toxic than alcohol and is a major cause of alcohol associated side effects
if acetylaldehyde is not efficiently converted into acetate severe toxicity can result
What is disulphiram (antabuse)?
inhibits breakdown of acetylaldehyde - used in alcoholics to induce an awful hangover to stop them drinkning
What is meant by zero order kinetics?
denotes a fixed metabolic rate as oppposed to the usual first order kinetic metabolism that 95% of drugs exhibit here metabolism is proportional to the concentration of the blood in your body
What is CYP2E1?
it is an inducible enzyme - heavy drinkers will induce it
in the presence of iron catalysts, produces powerful oxidants such as hydroxyl radicals
What does CYP2E1 induce?
a hypermetabolic state = increased re-oxidation of mitochondrial NADH => increased oxygen and ATP consumption
What levels of a substance is higher in chronic alcoholics?
higher levels of acetyaldehyde in tissues compared to non-alcoholics after a similar alcohol load, reflecting reduced hepatic ALDH activity seen in chronic drinkers both with and without liver disease
What does the CYP2E1 pathway produce?
generates reactive oxygen species
What happens if the redox homeostasis capacity of hepatocytes is overwhelmed?
metabolic disturbances occur:
1) lack of pyruvate for gluconeogenesis=> hypoglycaemia
2) NADH reducing agent for lipogenesis => steatosis
3) Pyruvate converted to lactate=> lactic acidosis
What does an increased NADH/NAD ratio cause?
inhibits gluconeogenesis and acetyl-coA is diverted from the citric acid cycle to ketogenesis and fatty acid synthesis
increased REDOX state inhibits fatty acid oxidation
this leads to increased triglyceride synthesis and reduced export as VLDL
What does increased NADH prevent the production of and what does this lead to?
prevents pyruvate being converted to glucose therefore favouring lactate and tricyleride by inhibiting mitochonidrial beta-oxiation of fatty acids
saturation of the TCA cycle prevents breakdown of acetate to CO2
How is alcohol related liver disease treated?
ABSTINENCE
- stopping drinking is the best thing to do
