Hepatitis - drug induced
Description
- Drug-induced liver injury (DILI) - a diagnosis of exclusion, classified by pattern using the R-value (ALT/ULN divided by ALP/ULN):
- Hepatocellular (R>=5) - ALT-predominant
- Cholestatic (R<=2) - ALP-predominant
- Mixed (R 2-5)
- Intrinsic (dose-dependent, predictable) - e.g. paracetamol - vs idiosyncratic (dose-independent, unpredictable, immune-mediated) - the majority of other drug causes
Epidemiology
- Paracetamol overdose - the commonest cause of acute liver failure in the Western world
- Idiosyncratic DILI - rare per individual drug exposure but antibiotics (esp. amoxicillin-clavulanate) are the commonest overall idiosyncratic cause in most series
- Herbal and complementary/dietary supplements - an increasingly recognised and often under-reported cause
Aetiopathogenesis
Intrinsic (predictable, dose-dependent)
- Paracetamol - saturated normal glucuronidation/sulfation pathways at supratherapeutic dose -> excess NAPQI (toxic metabolite) via CYP2E1 -> glutathione depletion -> centrilobular hepatocyte necrosis
- Risk increased by glutathione depletion states - malnutrition, chronic alcohol use, fasting
Idiosyncratic (unpredictable, immune-mediated or metabolic)
- Hepatocellular pattern: isoniazid, methyldopa, many NSAIDs
- Cholestatic pattern: amoxicillin-clavulanate, flucloxacillin, anabolic steroids, chlorpromazine
- Mixed pattern: many antibiotics, phenytoin
- Direct mitochondrial toxicity: sodium valproate, tetracyclines (esp. IV high-dose)
- Immune checkpoint inhibitors - a distinct immune-mediated hepatitis requiring corticosteroids rather than simple drug cessation alone
Diagnosis
Approach - exclusion-based
- Temporal relationship to a new drug (typically days-weeks for idiosyncratic reactions, can be delayed even after cessation)
- Exclude viral hepatitis (A/B/C/E), autoimmune hepatitis, biliary obstruction (ultrasound), ischaemic hepatitis, alcohol-related disease before attributing to a drug
- RUCAM (Roussel Uclaf Causality Assessment Method) score - structured causality assessment tool used in ambiguous cases
Paracetamol overdose specifically
- Serum paracetamol level plotted on the treatment nomogram (time since ingestion vs level) determines NAC treatment threshold for a single acute overdose - treat if level is above the treatment line, or empirically if timing/dose uncertain or staggered ingestion
- Hy's Law - ALT/AST >3x ULN plus bilirubin >2x ULN (without cholestasis/Gilbert's) predicts a substantially increased risk of severe/fatal DILI - a key marker of severity, not just abnormal LFTs
Management
A. Paracetamol overdose
- N-acetylcysteine (NAC) - replenishes glutathione, most effective if started within 8 hours of ingestion, but still given for later presentations/established injury - do not withhold based on time alone
- Activated charcoal if within 1-2 hours of a large ingestion
- Liver transplant unit referral (King's College Criteria) if progressing to acute liver failure - coagulopathy, encephalopathy, acidosis, renal impairment
B. Idiosyncratic DILI
- Stop the causative drug promptly - the single most important intervention; most idiosyncratic DILI improves with cessation alone
- Supportive care; monitor LFT trend to confirm resolution
- Avoid re-challenge with the same or cross-reactive agent once a clear causal link is established
C. Immune checkpoint inhibitor-associated hepatitis
- Hold the checkpoint inhibitor; corticosteroids for grade >=2 - a distinct immune-mediated mechanism requiring active immunosuppression rather than cessation alone
- Mycophenolate for corticosteroid-refractory cases; avoid infliximab (hepatotoxic itself)
D. Monitoring on high-risk drugs
- Baseline and periodic LFT monitoring for known hepatotoxic agents (isoniazid, methotrexate, valproate) - allows early detection and cessation before progression
Associations
- Chronic alcohol use, malnutrition, fasting - increase paracetamol/NAPQI toxicity risk
- Concurrent hepatotoxic drug combinations (e.g. isoniazid + rifampicin) - additive/synergistic risk
- Genetic polymorphisms (e.g. HLA associations) - underlie individual susceptibility to specific idiosyncratic reactions (isoniazid, flucloxacillin)
- Pre-existing liver disease - not always a prerequisite, but can worsen outcomes if DILI occurs
Natural history & complications
- Most idiosyncratic DILI resolves fully within weeks-months of stopping the causative drug
- Untreated significant paracetamol overdose - progression to fulminant hepatic failure, coagulopathy, encephalopathy, death without transplantation
- Hy's Law-positive cases carry a materially increased mortality risk and should prompt urgent specialist involvement
- A minority of DILI cases (particularly cholestatic) can become chronic with prolonged cholestasis or, rarely, progress to cirrhosis
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