M104 Alcohol metabolism symposia Flashcards

1
Q

Approximately what percentage of ingested ethanol is lost through breath/urine?

A

10%

the rest is metabolised

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2
Q

Is ethanol commonly found in adipose tissue?

A

no, very little

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3
Q

Where does the metabolism of ingested ethanol occur?

A

liver (nearly all)

brain, pancreas and stomach

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4
Q

What is the role of alcohol dehydrogenase?

A

it converts ethanol to acetaldehyde

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5
Q

Where does the conversion of ethanol to acetaldehyde occur?

A

in the cytosol of hepatic cells

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6
Q

What is the role of aldehyde dehydrogenase?

A

to convert acetaldehyde into acetate

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7
Q

Where does the conversion of acetaldehyde into acetate occur?

A

in the hepatic mitochondria

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8
Q

What happens to the acetate and some of the acetaldehyde in the hepatic mitochondria?

A

they are released into the circulation

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9
Q

What substances are responsible for the conversion of

ethanol to acetaldehyde?

A

Cytochrome P450 complexes, particularly CYP2E1 in the mitochondria
catalases (peroxisomes)

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10
Q

Why do chronic drinkers build up tolerance?

A

bc CYPs are inducible, so the more a person drinks, the more CYP2E1 is expressed and allows more metabolism of the alcohol

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11
Q

What is the CYP2E1 complex involved in?

A

paracetamol metabolism - converts paracetamol to a toxic intermediate, NAPQI

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12
Q

Why are chronic drinkers more susceptible to the effects of paracetamol toxicity?

A

bc CYP2E1 is expressed more in chronic drinkers, and it converts paracetamol to a toxic intermediate
NAPQI

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13
Q

What is responsible for people’s bodies having different capacities for processing alcohol?

A

bc people have different concentrations of alcohol dehydrogenase, which is the first enzyme catalysing the conversion of ethanol to acetaldehyde

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14
Q

What is an example of a group of people that process alcohol differently to others?

A

individuals of Asian descent who have the B2 ADH isoform metabolise alcohol 20% faster than those who possess the B1 isoforms, which is present in Northern Europeans

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15
Q

What is the isoform responsible for some Asian people metabolising alcohol differently to northern EU’s?

A

the B2 ADH isoform

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16
Q

What is the role of polymorphisms?

A

they affect how efficiently acetaldehyde is able to be cleared

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17
Q

Why might some people with certain polymorphisms have different tolerances to the effects of alcohol?

A

certain polymorphisms will result in the build up of acetaldehyde is responsible for some of the toxic effects of alcohol

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18
Q

What are some of the toxic effects of alcohol?

A

nausea, vomiting and headaches

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19
Q

What is an effect on the body caused by acetaldehyde build up?

A

flushing

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20
Q

What might be an effect in people who have less efficient ALD enzymes?

A

they may have a distaste for alcohol

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21
Q

What is the effect of the alcohol dehydrogenase and aldehyde dehydrogenase reactions on the redox state?

A

NAD is reduced to NADH

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22
Q

What ratios are increased when the amount of NADH and alcohol metabolised increases?

A

the lactate : pyruvate ratio

the beta-hydroxybutyrate : acetoacetate ratio

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23
Q

What is the relationship between the metabolism of alcohol and the amount of NADH produced?

A

the more metabolised alcohol there is, the higher proportion of NADH there is

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24
Q

Why does an increase in metabolised alcohol result in a higher proportion of NADH?

A

the conversion of ethanol to acetaldehyde and the conversion of acetaldehyde to acetate are coupled to the reduction of the cellular NAD+ to generate NADH

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25
Q

What processes are decreased when the amount of NADH and alcohol metabolised increases?

A

Glycolysis
Citric acid cycle – ketogenesis
FA oxidation
Gluconeogenesis

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26
Q

What happens when the amount of NADH and alcohol metabolised increases?

A

the redox potential of the cells is changed

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27
Q

What toxic effect is caused by alcohol on a cellular level?

A

oxidant stress

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28
Q

What are the effects of oxidant stress on a cellular level?

A

acute tissue damage and fibrosis is associated with lipid peroxidation
the FRs attack cellular and mitochondrial DNA, causing deletion mutations and genomic instability

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29
Q

What does the metabolic pathway of methanol have in common with that of ethanol?

A

it uses the same enzymes but it generates different intermediates

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30
Q

What are the stages of the metabolic pathway of methanol?

A

methanol (+ alcohol dehydrogenase) < formaldehyde (+ aldehyde dehydrogenase) < formic acid (+ folate) < CO2 + H2O

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31
Q

What are the intermediates of the metabolic pathway of methanol?

A

formaldehyde, formic acid

32
Q

What are the end products of the metabolic pathway of methanol?

A

CO2 + H2O

33
Q

What are the enzymes involved in the metabolic pathway of methanol?

A

alcohol dehydrogenase
aldehyde dehydrogenase
folate

34
Q

Why can ingestion of methanol can be very serious?

A

bc in the body, via the metabolic pathway of methanol, formic acid is produced

35
Q

What types of ingestion of methanol are there?

A

deliberate or accidental

36
Q

What pH is formic acid?

A

pH 2-3

37
Q

What are some of the effects of methanol ingestion?

A

blindness (the destruction of the optic nerve)

38
Q

What quantity of ingested methanol would be sufficient enough to cause blindness?

A

as little as 10 mls

39
Q

What would be the effect of 30mls of ingested methanol?

A

is potentially fatal

40
Q

What is the scientific name of antifreeze?

A

or antifreeze also uses the same enzymes and alcoh

41
Q

What does the metabolic pathway of ethylene glycol have in common with that of ethanol?

A

uses the same enzymes

42
Q

What are the stages of the metabolic pathway of ethylene glycol?

A

ethylene glycol (+ alcohol dehydrogenase) < glycoaldehyde (+ aldehyde dehydrogenase) < glycolic acid (+ lactate dehydrogenase + glycolic acid oxidase) < four final products via two enzymes

43
Q

What are the intermediates of the metabolic pathway of ethylene glycol? (EG.GA)

A

ethylene glycol
glycoaldehyde
glycolic acid

44
Q

What are the end products of the metabolic pathway of ethylene glycol? (GOF.ab)

A

glycine
oxalate acid
formic acid
a-hydroxy - b-ketoadipate

45
Q

What are the enzymes involved in the main parts of the metabolic pathway of ethylene glycol?

A

alcohol dehydrogenase, aldehyde dehydrogenase

lactate dehydrogenase + glycolic acid oxidase

46
Q

What substances are involved in the final parts of the metabolic pathway of ethylene glycol?

A

pyridoxine

thiamine

47
Q

What are the effects of the toxicity of ethylene glycol?

A

acidosis
its downstream metabolites can affect heart, CNS and cause kidney failure
can be fatal

48
Q

What is the role of fomepizole?

A

it acts as a competitive inhibitor of alcohol dehydrogenase

49
Q

What is fomepizole used to treat?

A

treats methanol and ethylene glycol overdose as it can prevent the formation of a toxic intermediates

50
Q

If both ethanol and ethylene glycol were co ingested, which would be metabolised over the other?

A

the ethanol would be preferentially metabolised bc alcohol dehydrogenase has 100x greater affinity for ethanol than it does ethylene glycol

51
Q

What can ethanol can be used as a treatment for?

A

ethylene glycol overdose if there is no access to an fomepizole

52
Q

What quantity of pure ethanol is in one unit of alcohol?

A

10 mls or 8g

53
Q

How do you find out the number of units in a drink?

A

( % alcohol x VOLUME ) / 1000

54
Q

What was the safe weekly drinking limit in 2016?

A

14 units / week for both genders, spread across three times a week

55
Q

What is the legal blood ethanol limit for driving in the UK?

A

less than or = to 80 mg / dL
≤ 2-3 units in female
≤ 3-4 units in men

56
Q

What is a metabolic consequence of chronic drinking?

A

alcoholic ketoacidosis

57
Q

What is the cause of alcoholic ketoacidosis?

A

the combined effect of the drinking and usually starvation state on glucose metabolism

58
Q

What is the pathophysiology behind alcoholic ketoacidosis?

A

Glycogen depletion / inhibited gluconeogenesis
Lipolysis and ketones increased (beta hydroxybutyrate) Insulin suppressed
Extracellular volume depletion/dehydration/stress - increase counter regulatory hormones further supressing insulin

59
Q

How does ethanol cause hypoglycaemia?

A

decreased intake of glucose (CHO)
depletion of glycogen
blockade of gluconeogenesis

60
Q

How is fatal hypoglycaemia treated?

A

Prompt treatment with glucose is life-saving
parenteral thiamine to prevent CNS damage in case there is also thiamine deficiency
there’s often a need to correct co-occurring electrolyte disturbances

61
Q

What are some of the endocrine complications of alcohol misuse?

A

a decreased testosterone and testicular atrophy
pseudo Cushing’s (tends to resolve with alcohol absitenence)
Metabolic Syndrome and Dyslipidaemia

62
Q

What nutritional issues are associated with alcohol misuse?

A
Low calcium (diet, decreased vitamin D)
Low phosphate (diet, increased PTH)
Low Mg, K (diet, urinary loss, hyperaldosteronism)
63
Q

What are typical liver function tests used?

A

Gamma Glutamyl Transferase
Transaminases (ALT and AST)
Globulin levels
Bilirubin & INR levels

64
Q

When is Gamma Glutamyl Transferase induced in the liver?

A

when alcohol consumption increases

65
Q

What are the two Transaminases used to test for liver function?

A

ALT and AST

66
Q

When are Transaminases induced in the liver?

A

these hepatic enzymes are increased due to hepatocellular damage that occurs when drinking occurs

67
Q

What substances ics / dcs when the liver becomes more cirrhotic?

A

there is a decrease in the albuminn and an increase in the globulin fraction

68
Q

What is the effect of clotting disturbances on the levels of substances?

A

bilirubin increases and increased INR

a decrease in albumin

69
Q

What are causes of a thiamine deficiency?

A

Ethanol interferes with GI absorption
Hepatic dysfunction, which hinders storage and activation
Malnourishment

70
Q

What are additional relevant blood tests for liver function?

A

Macrocytosis – raised MCV in a full blood count
Raised serum ferritin concentration
Hyperuricaemia
Hypertriglyceridaemia
Increased carbohydrate-deficient transferrin or CDT

71
Q

When is a full blood count used when testing for liver function?

A

macrocytosis or macrocytic anaemia

72
Q

What does a carbohydrate deficient transferrin measurement indicate?

A

a patient’s recent alcohol ingestion over the last seven to 14 days

73
Q

How does alcohol affect the post translational modifications of the transferrin molecule?

A

if there’s a lot of alcohol ingestion, results in a transferrin molecule that doesn’t have all the carbohydrates attached to it - so it’s a carbohydrate deficient transferrin

74
Q

Which test is used by the DVLA for liver function?

A

carbohydrate deficient transferrin

75
Q

What is the relationship between alcohol mis-use and hypertension?

A

it can lead to hypertension, which will have an effect on cardiovascular risk

76
Q

What are the mechanisms that are potentially behind the causation of hypertension from alcohol mis-use?

A

impairment of the baroreceptors (which sense blood pressure)
increase of sympathetic activity
stimulation of the renin-angiotensin-aldosterone system
an increase in plasma cortisol
an increase of intracellular calcium with subsequent increase in vascular reactivity
endothelial e.g. inhibition of endothelium-dependent nitric oxide production