paracetamol overdose

Question 1

what is the cause of death in PO?

Answer 1

cell death caused by necrosis from a toxin - the clinical effects therefore come from the loss of function of cells

Question 2

why may the effects of PO vary?

Answer 2

it depends on the proportion of cells that are affected and the function remaining to meet the demand of the organ

Question 3

what is another name for paracetamol?

Answer 3

acetaminophen

Question 4

what is the prevalence of PO?

Answer 4

48% of all medical admissions and 10000 per year
the commonest cause of medical admissions in under 40s
leading cause for liver failure acutely

Question 5

what is the affect of PO?

Answer 5

causes severe injury to the liver, abdo pain, very unwell after 40 hours

Question 6

how would you identify the cause?

Answer 6

the social and medical history

if alcohol then take the amount and the strength to calculate the units

Question 7

what is the relationship between strength and units?

Answer 7

1 litre of the APV = the number of units

Question 8

how may PO cases present?

Answer 8

comatosed, acidotic, renal failure, clotting disturbance, ALT far higher than usual such as 1500 when should be <35

Question 9

what ligaments are in the liver?

Answer 9

the falciform anteriorly separating the left and right loves, the teres posteriorly, the right and left triangular and the coronary ligament posteriorly

Question 10

what does the gall bladder feed into?

Answer 10

the common bile duct

Question 11

what is the lobe inferior to the gall bladder?

Answer 11

the quadrate lobe - the caudate is superior to this

Question 12

what is the exit for the HAP, and PV?

Answer 12

the porta hepatis

Question 13

what comes off the IVC?

Answer 13

the hepatic veins

Question 14

what is the structure of the liver?

Answer 14

it is the largest organ in the body weighing around 1.2-1.5kg and is 2.5% of the body mass. There are two blood supplies from the gut and the artery

Question 15

outline the blood supplies to the liver?

Answer 15

the portal vein comes from the gut and carries 2/3 volume but low pressure blood, the blood from the hepatic artery is oxygenated and higher pressure

Question 16

why is two supplies beneficial?

Answer 16

it is less susceptible to ischaemia

Question 17

what are the metabolic functions and some examples of the liver?

Answer 17

carbohydrate (glycogenesis), fat (triglyceride and lipoprotein), amino acid metabolism, protein and amino acid synthesis (albumin, CRP), hormones and prohormones (angiotensin), detoxification (alcohol, medication, drugs, chemicals), activation of drugs and bilirubin metabolism

Question 18

what other functions does the liver have?

Answer 18

barrier to sepsis and vitamin A, D and B12 and iron storage

Question 19

what is the histological structure of the liver?

Answer 19

the blood runs along sinusoids into the hepatic vein, the cells are square shaped and the hepatocytes are close to a blood supply, there is lots of mitochondria, ER and cytoplasm for lots of enzymes

Question 20

how can liver be affected by drugs?

Answer 20

there are two ways:
intrinsic - everyone will react in the same way - will damage all livers in high volumes
idiosyncratic - unexpected and uncharacteristic - most reactions - rare and unpredictable

Question 21

what are the differences between individuals metabolism?

Answer 21

the liver has evolved to detoxify the blood and make toxins safe, then excrete them. There are many different enzymes and metabolic pathways and people differ in the way that they metabolise things

Question 22

how does paracetamol metabolism work?

Answer 22

it is attached to sulphuric acid which makes it water soluble and then excretes it by the kidneys or is conjugated with glucuronide. A minor pathway will metabolise paracetamol when a large amount is taken

Question 23

what causes damage in overdose?

Answer 23

NAPQI

Question 24

how can NAPQI cause damage?

Answer 24

the ability to detoxify NAPQI is overwhelmed. This means that it cannot be turned into cysteine and mercapturic acid conjugates and that it builds up and attaches to cell proteins to cause damage

Question 25

what is the reaction for paracetamol metabolism?

Answer 25

paracetamol will be conjugated wither into sulfate or glucuronide. If not it will go through the P450 pathway and make N-acetyl-p-benzoquinoneimine which is toxic. This with glutathione will make cysteine and mercapturic acid conjugates which are non toxic

Question 26

what is the mechanism of cell death in viral hepatitis and what does it look like?

Answer 26

apoptosis - controlled and programmed - occasional dead cells with dense pink cytoplasm and small nucleus

Question 27

what is the mechanism of death in PO and what does it look like?

Answer 27

confluent necrosis - uncontrolled - lost all proteins, pink - hepatocytes first as these have the enzymes that metabolise paracetamol

Question 28

what causes acute liver failure?

Answer 28

over 50% of cells with a loss of function/death

Question 29

which liver cells die first?

Answer 29

the zone 3 ones as they contain the metabolising enzymes

Question 30

what are the effects of cell death in the liver?

Answer 30

amino transferase enzymes will peak at around 1000-3000
jaundice - cannot process bilirubin
coma - failure to detoxify nitrogenous compounds
bleeding - failure to synthesis proteins and clotting factors
renal failure - lower glomerular filtration due to shock - hepatorenal syndrome

Question 31

what is important in PO treatment?

Answer 31

early treatment - delayed presentation and staggered overdose gives poorer outcomes

Question 32

how do you treat PO?

Answer 32

the dose is calculated based on the body weight - activated charcoal at 150mg/kg makes the patient vomit and remove any paracetamol
N acetyl cysteine IV (or methionine orally if allergic) to give glutathione to mop NAPQI up
test level of paracetamol after 4 hours to identify treatment and risk

Question 33

how does NAC make glutathione?

Answer 33

N-acetylcysteine - L-cysteine-glutathione

Question 34

what are the amino transferase enzymes detected by?

Answer 34

ALT and AST through lab tests

Question 35

what is the major component of jaundice?

Answer 35

conjugated hyperbilirubinaemia

Question 36

what does failure to detoxify nitrogenous compounds lead to and why?

Answer 36

coma - hepatic encephalopathy due to circulation of excitatory AAs

Question 37

what factors are depleted in a bleeding tendency in liver failure?

Answer 37

Factors II, VII, IX and X

Question 38

what is the ITU management for PO?

Answer 38

continue the NAC, intubated, sedated and ventilated with filtration for the kidneys which helps to repair damage and improves prognosis. They will need feeding and ABs/AFs as fungal sepsis is the biggest killer in PO. Only correct clotting if they are bleeding and simultaneously carry out the work up towards the liver transplantation

Question 39

what needs to be considered for transplantation?

Answer 39

kings college criteria, the elective and urgent lists, the mode (living donor, split, OLT, auxiliary or domino), units and volume of work load and ethical issues