paracetamol-induced liver disease

what are the two most common uses of paracetamol?

- anti-pyretic
- analgesic

what is an anti-pyretic?

reduces fever

what is another name for paracetamol?

acetaminophen

what is involved in the risk assessment of paracetamol overdose? (6)

- date of ingestion
- timing of ingestion - single/staggered overdose
- weight
- pregnancy - use pre-pregnancy weight
- total amount ingested (mg/kg)
- current suicidal risk

what are the risks of doses <75mg/kg?

unlikely to be toxic unless taken staggered

what are the risks of doses > 150mg/kg?

serious or fatal adverse effects

what are the risk of total dose > 12g?

potentially fatal

what is acute ingestion?

ingesting the potentially toxic dose within one hour or less

what is staggered ingestion?

excessive ingestion over a period longer than one hour

how is paracetamol usually eliminated? (2)

- conjuagte with glucoronic acid or sulfate in the liver
- excreted thorugh kidney

what happens in paracetamol overdose? (2)

- capacity of normal conjugation pathway is overwhelmed
- paracetamol oxidised by a liver P450 cytochrome C to N-acetyl-benzoquinoeimine (NABQI)

what happens usually to NABQI?

conjugated by addition of glutathione which is renally excreted

what happens to NABQI in paracetamol overdose? (3)

- glutathione stores are depleted
- excess NABQI binds to hepatocellular proteins resulting in oxidative damage + mitochondrial dysfunction
- leads to hepatocellular injury

how does NABQI bind to hepatocellular proteins?

through cysteine aa side chains

what may a patient experience 12-36 hours following a paracetamol overdose?

abdominal pain

what may a patient experience 48-72 hours following a paracetamol overdose? (6)

clinical features due to hepatic necrosis:
- right upper quadrant pain
- nausea
- vomiting
- jaundice
- acute kidney injury
- hepatic encephalopathy (HE)

what are the symptoms of paracetamol overdose? (8)

- asymptomatic (first 24 hours)
- nausea + vomiting
- weight loss
- malaise
- abdominal pain
- altered mental status
- confusion
- scars (from previous self-harm)

what are the signs of paracetamol overdose? (7)

- asterixis
- bruising
- jaundice
- right upper quadrant tenderness
- oliguria/anuria
- tachycardia/hypotension
- coma

what is anuria?

lack of urine production

what is oliguria?

low urine output

what is the diagnosis of paracetamol overdose primarily based on?

history

what test would be used to assess for hepatic damage, extrahepatic organ dysfunction and determine which patients need urgent referral?

blood test

what would the blood test involve? (8)

- full blood count
- urea + electrolytes
- liver function tests
- bone profile
- venous/arterial blood gas
- blood glucose
- paracetamol levels
- salicylate levels

what would be found on ABG?

lactic acidosis

why does paracetamol overdose cause lactic acidosis?

NAPQI inhibits aerobic respiration

what graph can be used to assess paracetamol concentration levels?

nonogram

what is on the x axis of the nonogram?

time (hours)

what is on the y axis of the nonogram?

plasma paracetamol concentration (mg/L)

what is the nonogram used to determine?

if treatment with N-acetylcysteine (NAC) is needed

what happens if the paracetamol concentration lies on or above the treatment line?

N-acetylcysteine should be administered

what is the main mechanism of action for N-acetylcysteine? (3)

- precursor to glutathione
- therefore increases glutathione concentration
- more glutathione available to bind to NAPQI

how is N-acetylcysteine administered in paracetamol overdose?

intravenously

how many consecutive infusions are normally given?

3

how is the first infusion given?

150mg/kg body weight over 1 hour

how is the second infusion given?

50mg/kg over next 4 hours

how is the third infusion given?

100mg/kg over next 16 hours

what can be an adverse effect of N-acetylcysteine?

anaphylactoid reaction

what is an anaphylactoid reaction?

NON-IgE mediated mast cell release

what should happen if patient experiences anaphylactoid reaction?

- temporarily stop infusion
- maybe antihistamine
- nebulised salbutamol

what does the management of patients with paracetamol overdose depend on?

timing of presentation:
< 8 hours
8-24 hours
> 24 hours

when should you start N-acetylcysteine immediately?

- staggered dose (taken over more than an hour) or unknown timing of intake
- presentation of 8-24 hours if dose > 150mg/kg
- presentation of >24 hours if jaundice/hepatic pain/raised ALT

what should be given if pt is presenting <1 hour?

activated charcoal

what can paracetamol overdose lead to?

acute liver failure

what are the liver transplant criteria?

- arterial pH <7.3, 24 hours after ingestion
or all of the following:
- prothrombin time > 100s
- creatinine > 300
- grade III or IV encephalopathy

which patients are at higher risk of developing hepatotoxicity?

- pts taking cytochrome p450 enzyme inducing drugs (chronic alcohol excess, carbamezapine, St John's wort, rifamipicin, phenytoin)
- malnourished patients (anorexic)

what is the best prognostic marker for liver failure in paracetamol overdose?

prothrombin time