Drug-induced liver injury

Overview

Drug-induced liver injury (DILI) is the leading cause of acute liver failure in the UK and a diagnosis of exclusion - recognition depends on a thorough drug history and systematic exclusion of other causes.

Pathophysiology

Intrinsic vs idiosyncratic DILI
FeatureIntrinsicIdiosyncratic
PredictabilityPredictable, dose-dependentUnpredictable, dose-independent
OnsetHours (e.g. paracetamol overdose)Weeks to months after starting drug
MechanismDirect hepatocyte toxicity (NAPQI depletes glutathione → zone 3 necrosis)Immune-mediated or metabolic in susceptible minority
ExamplesParacetamolAmoxicillin-clavulanate, flucloxacillin, nitrofurantoin, isoniazid
⚠️
Herbal and dietary supplements are a growing cause of DILI - always ask specifically; patients do not consider them 'medications'.

Presentation

•Asymptomatic - incidental LFT elevation (common)
•Symptomatic - fatigue, nausea, anorexia, RUQ discomfort, jaundice
•Cholestatic features - pruritus, dark urine, pale stools
•Hypersensitivity triad - fever, rash, eosinophilia (immune idiosyncratic reaction)
•Severe disease - encephalopathy, coagulopathy, INR >1.5 → acute liver failure
🚨
Hy's Law: ALT/AST >3x ULN AND bilirubin >2x ULN (no cholestasis, no other cause) = ~10% mortality; requires urgent specialist review.

Investigations

🥇 First-line

•LFTs (ALT, AST, ALP, GGT, bilirubin, albumin) - calculate R-ratio; PT/INR - most sensitive marker of synthetic function; FBC - eosinophilia suggests hypersensitivity; paracetamol level (if overdose suspected) - plot on treatment nomogram; viral hepatitis screen (HAV IgM, HBsAg, HBcAb, HCV Ab, EBV/CMV); autoimmune screen (ANA, ASMA, AMA, immunoglobulins); abdominal ultrasound - exclude biliary obstruction

🥈 Second-line

•liver biopsy - if diagnosis uncertain after non-invasive workup (no pathognomonic finding for DILI)
•Gold standard for causality attribution: RUCAM scoring - score >8 = highly probable DILI

Management

🥇 First-line

•withdraw causative drug immediately - cornerstone of management; LFT improvement within 30-60 days confirms diagnosis (de-challenge response)
•Paracetamol overdose: N-acetylcysteine (NAC) IV - replenishes glutathione, prevents NAPQI accumulation; most effective within 8-10 hours, still beneficial up to 24 hours; dose guided by nomogram
•Supportive care: IV fluids, nutritional support, treat coagulopathy and encephalopathy; admit if acute liver failure

🥈 Second-line

•ursodeoxycholic acid - persistent cholestatic DILI/pruritus; corticosteroids - hypersensitivity-mediated DILI (fever, eosinophilia, rash) or drug-induced autoimmune hepatitis

🥉 Third-line

•liver transplantation - acute liver failure meeting Kings College Criteria (paracetamol: pH <7.3, OR creatinine >300 micromol/L + PT >100 seconds + grade III-IV encephalopathy); refer early to specialist liver unit
⚠️
Do not re-challenge a patient with a drug that caused clinically significant DILI (especially if jaundice or hepatocellular pattern) - risk of more severe, potentially fatal recurrence. Document clearly and communicate to patient and GP.

Prognosis

•Most recover within 1-3 months (hepatocellular) or 3-6 months (cholestatic) after drug withdrawal
•Jaundice with hepatocellular injury (Hy's Law) → ~10% mortality
•~5-10% develop chronic liver disease (>6 months); more common with cholestatic pattern
•Paracetamol-induced ALF treated promptly with NAC has substantially improved outcomes

Classification by R-ratio

R = (ALT / ULN) ÷ (ALP / ULN). R ≥5 = hepatocellular; R ≤2 = cholestatic; R 2-5 = mixed.

•Hepatocellular - paracetamol, isoniazid, nitrofurantoin, statins
•Cholestatic - amoxicillin-clavulanate, flucloxacillin (often delayed weeks after stopping), anabolic steroids

LFT Monitoring for High-risk Drugs

Drugs requiring LFT surveillance
Methotrexate - baseline + regular monitoring; cumulative fibrosis risk
Isoniazid - monthly LFTs; high risk in elderly, alcohol users, HIV
Statins - baseline LFTs; >3x ULN is contraindication to starting
Amiodarone - hepatocellular injury, cirrhosis with long-term use
Azathioprine - regular FBC and LFTs, especially first months
Paracetamol - max 4 g/day adults; reduce in frailty, low body weight, alcohol excess