Hepatoxicity

Question 1

How many drugs are associated with hepatoxicity?

Answer 1

900 drugs, toxins and in particular herbal remedies have the ability to cause liver injury.

Question 2

What are some of the statistics regarding drug induced hepatoxicity?

Answer 2

Drugs are responsible for:
20-40% of liver failure
2-5% of hospitalised jaundice
10% of acute hepatitis

Question 3

How can the severity of liver injury be reduced?

Answer 3

Early detection and hence stopping the medication responsible for causing liver injury. This reduces the severity of injury.

Question 4

Examples of drugs that have been withdrawn due to ability to cause hepatoxicity.

Answer 4

Troglitazone
Nefazodone
Ximelagatran

Question 5

What are the risk factors for drug induced hepatoxicity?

Answer 5

Age
Sex - females are twice as likely
Alcohol ingestion
Pre-existing liver diseases
Genetics
Co-morbidities - HIV
Drug formulation

Question 6

What ages are particularly vulnerable to liver toxicity?

Answer 6

Elderly - due to being on more medications and are more likely to have existing co-morbidities

Children - sodium valproate induced hepatoxicity has an increased risk in under 3s, aspirin is contra-indicated in those under 16 due to risk of Reye’s syndrome which is a type of hepatoxicity

Question 7

What are the different pathophysiological mechanisms underlying drug induced hepatoxicity?

Answer 7

Disruption of hepatocytes
Disruption of transport proteins
Cytolytic T cell activation
Apoptosis of hepatocytes
Mitochondrial disruption
Bile duct injury

Question 8

Briefly outline the classification of drug toxicity mechanisms.

Answer 8

Type A ADRs are intrinsic or predictable which have demonstrated a similar injury in animals either drug to the drug or its metabolite.
These types of ADRs are responsible for 80% of all ADRs

Type B are idiosyncratic or unpredictable producing a hypersensivity or immunoallergenic reaction or if the metabolite is responsible then a metabolic idiosyncratic.
An example include phenytoin induced rash or fever.

Question 9

What is an important consideration regarding drugs and LFTs?

Answer 9

Many drugs are known to cause a rise in LFTs - up to 2x the upper reference range. These are known as inconsequential rises and no interventions have to be made.

Question 9

Which LFTs results suggest liver damage has occurred?

Answer 9

Elevated ALT greater than 2x the upper limit of normal
Elevated conjugated bilirubin to greater than 2x upper limit of normal
Combined elevated ALP and total bilirubin with one greater than 2x the upper limit of normal
Or if there are other symptoms of liver disease present

Question 10

Outline the appropriate management of drug induced hepatoxicity.

Answer 10

Drug withdrawal
Offer an antidote if available or appropriate (for example acetylcysteine in paracetamol overdose)
Corticosteroids may be considered if signs of hepatoxicity remain after 6 months or if patient is still deteriorating 3 weeks after stopping the drug
Supportive therapy depending on side effects of the hepatoxicity
Reporting via the yellow card scheme as hepatoxicity is classified as serious

Question 11

How can drug induced hepatoxicity be prevented?

Answer 11

Implementing and ensuring LFT monitoring
Patient education - advising on potential symptoms indicating hepatoxicity
Appropriate OTC counselling about the risks of LD with paracetamol, health food products and herbal remedies.

Question 12

When does paracetamol induced hepatoxicity occur?

Answer 12

In overdose including patients below 50kg

And where there is misuse in at risk populations this includes patients on enzyme inducers and who consume a lot of alcohol which increases the risk of toxicity

Question 13

What percentage is paracetamol responsible for acute liver failure?

Answer 13

In 50% of the cases

Question 14

What doses of paracetamol leads to the different types of liver failure?

Answer 14

> 15g leads to fatal hepatic necrosis
7.5g – risk of severe liver damage
5g requires hospital admission and observation (only 1 gram above maximum daily recommended amount)

Question 15

When does phase I hepatoxicity occur?

Answer 15

0.5 - 24 hours after ingestion
If a patient presents 12 hours later the antidotes are less effective

Question 16

What are the symptoms that occur in phase I hepatoxicity?

Answer 16

Asymptomatic or anorexia, nausea, vomiting, malaise

Question 17

When does phase II hepatoxicity occur?

Answer 17

18-72 hours after

Question 18

What are the symptoms that occur in phase II hepatoxicity?

Answer 18

Right upper quadrant pain and tenderness
Anorexia
Nausea
Vomiting
Possibly oliguria (urinary output less than 400 ml per day or less than 20 ml per hour)

Question 19

When does phase III or hepatic phase occur?

Answer 19

72-96 hours after

Question 20

What are the symptoms that occur in phase III hepatoxicity?

Answer 20

If left untreated:
Continued symptoms, hepatic necrosis may be seen as jaundice, coagulopathy, hypoglycemia, hepatic encephalopathy, possible acute renal failure, death from multiorgan failure

Question 21

When does phase IV or hepatic phase occur?

Answer 21

This is complete resolution which if treated, occurs 4 days to three weeks afterwards

Question 22

Describe the paracetamol metabolic pathways.

Answer 22

95% of Paracetamol undergoes glucuronidation which is then simply excreted in the urine.

5% of Paracetamol however undergoes CYP450 metabolism producing toxic N-acetyl p-benzoquinone imine. Usually this isn’t a problem when there is sufficient glutathione available for conjugation, again resulting in the excretion of the metabolite. However when glutathione levels becomes depleted due to overdose as more paracetamol enters this pathway this results in N-acetyl p-benzoquinone imine accumulating and binding directly to the hepatocytes resulting in fatal liver damage.

Question 23

What can be given within an hour of suspected paracetamol overdose?

Answer 23

Can give activated charcoal which results in the removal of unabsorbed paracetamol from the gut.

Question 24

Which specific drugs are given in paracetamol overdose?

Answer 24

First line: IV Acetylcysteine, ideally given within 8 hours of overdose
or PO Methionine

Both work by replenishing glutathione levels

Question 25

What specific dose of acetylcysteine should be given?

Answer 25

The dose is based on the serum paracetamol level.
The are projected treatment lines and then a lower one for patients at an enhanced risk, for example on enzyme inducers, chronic alcoholics or malnourished patients.

Question 26

Up to what time can acetylcysteine be given?

Answer 26

Ideally give within 8 hours, effectiveness reduced after 12 hours but can be given up to 24 hours.