Drug-Induced Liver Injury Patterns and Clinical Management
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Direct answer
Drug-induced liver injury is liver damage caused by a medicine, herbal product or toxin, and it is classified as hepatocellular, cholestatic or mixed using the R ratio. Stopping the offending drug is the cornerstone of management, while paracetamol overdose has a specific antidote. Hy's law identifies injuries that carry a serious risk of death.
What you must remember
- R ratio: ALT divided by ALP, each as a multiple of the upper limit of normal; above 5 is hepatocellular, 2 to 5 is mixed, and 2 or less is cholestatic.
- Hepatocellular drugs: Paracetamol overdose, isoniazid, valproate, ketoconazole and nevirapine, with transaminases dominating the picture.
- Cholestatic drugs: Amoxicillin-clavulanate, flucloxacillin, oral contraceptives, anabolic steroids and chlorpromazine, with raised ALP and bilirubin.
- Mixed injury: Phenytoin, carbamazepine and sulfonamides such as co-trimoxazole.
- Hy's law: ALT above three times normal with bilirubin above twice normal, without a marked ALP rise, signals a serious risk of death, historically about one in ten.
- Isoniazid risk factors: Age over 35, heavy alcohol use, slow acetylator status and concurrent hepatotoxic drugs.
A worked pattern: hepatitis during antitubercular treatment
A 38-year-old man with alcohol use is four weeks into rifampicin, isoniazid, pyrazinamide and ethambutol. He develops nausea, anorexia and jaundice, with ALT five times the upper limit, ALP 1.2 times the upper limit and raised bilirubin.
- Calculate the R ratio: Calculated at presentation rather than on a trend, 5 divided by 1.2 gives about 4.2, a mixed pattern.
- Stop the drugs: Because the injury is symptomatic with a significant transaminase rise, the drugs are stopped and liver function is followed closely.
- Find the likely culprit: Isoniazid and pyrazinamide are the usual suspects. Alcohol is stopped, and the injury is documented as a suspected adverse drug reaction.
- Rebuild the regimen: National programme guidance governs how the regimen is rebuilt once the liver recovers, usually by reintroducing one drug at a time. Most schedules restart rifampicin first, then isoniazid, and leave pyrazinamide for last or omit it, though books differ on the exact order.
- Exclude other causes: Viral serology, autoimmune markers and imaging are added, because drug injury is a diagnosis of exclusion as well as a pattern.
Where the examiner pins the pattern
Most drug-induced liver injury traps are about pattern recognition.
- Trap: confusing cholestatic and hepatocellular drugs. Correct: amoxicillin-clavulanate causes cholestatic injury with raised ALP and bilirubin that can appear weeks after starting, whereas paracetamol gives a hepatocellular pattern with very high early transaminases.
- Trap: treating Hy's law as a statement about the cause. Correct: it predicts seriousness rather than cause, so examiners give the ALT and bilirubin values and expect you to recognise the risk, not name the drug.
- Trap: assuming a drug caused an enzyme rise. Correct: causality is assessed with a structured method such as RUCAM, and the timing of dechallenge and rechallenge matters.
Frequently asked questions
Which drug is a classic cause of cholestatic drug-induced liver injury?
Amoxicillin-clavulanate is a classic cause of cholestatic drug-induced liver injury, with raised alkaline phosphatase and bilirubin that may appear weeks after starting the antibiotic. Flucloxacillin is another classic example of cholestatic injury in exam questions.
Which antitubercular drug causes the most hepatotoxicity?
Isoniazid is the commonest antitubercular drug implicated in hepatotoxicity, although pyrazinamide is often called the most intrinsically hepatotoxic. Isoniazid risk is higher in patients over 35, heavy alcohol users and slow acetylators. Rifampicin also contributes to combined liver injury during intensive treatment.
What is Hy's law in drug-induced liver injury?
Hy's law states that ALT above three times the upper limit of normal, with total bilirubin above twice the upper limit and no marked ALP rise, predicts serious drug-induced liver injury. Historically, about one in ten patients with this pattern died or needed transplantation.
What is the antidote for paracetamol hepatotoxicity?
N-acetylcysteine is the antidote for paracetamol hepatotoxicity, because it replenishes glutathione and neutralises the toxic metabolite NAPQI. It is most effective when started within eight hours of ingestion.