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Drug-Induced Liver Injury (DILI)
Liver damage caused by prescription/OTC drugs, herbs, or supplements.
Liver functions relevant to DILI
Drug metabolism (Phase I & II), detoxification, bile production, protein synthesis (e.g. albumin, clotting factors).
First-pass effect
High exposure of liver to orally-administered drugs → increased susceptibility to injury.
Intrinsic DILI
Predictable, dose-dependent (e.g. paracetamol overdose).
Idiosyncratic DILI
Unpredictable, not dose-related (e.g. isoniazid, amoxicillin-clavulanate).
Direct hepatocellular toxicity
Drug or metabolite directly damages hepatocytes (e.g. paracetamol via NAPQI accumulation).
NAPQI (N-acetyl-p-benzoquinone imine)
Toxic metabolite of paracetamol; normally detoxified by glutathione.
Glutathione depletion
Leads to NAPQI accumulation → binds proteins → hepatocyte death → centrilobular necrosis.
Immune-mediated liver damage
Drug/metabolite forms hapten → activates immune cells → inflammation ± autoimmune reaction.
Drugs causing immune-mediated DILI
Isoniazid, phenytoin, carbamazepine, antibiotics.
Immune-mediated features
Fever, rash, eosinophilia, not dose-related.
Mitochondrial dysfunction
Drugs impair ATP production or increase ROS → steatosis, necrosis.
Drugs causing mitochondrial DILI
Valproate, tetracyclines, antiretrovirals (e.g. didanosine).
Microvesicular steatosis
Small fat droplets in hepatocytes due to mitochondrial dysfunction.
Genetic predisposition
CYP450 polymorphisms, HLA-B*5701 (flucloxacillin DILI risk).
Age extremes
Elderly: polypharmacy + reduced hepatic reserve.
Neonates: immature enzyme systems.
Sex-based risk
Females may have higher risk of immune-mediated DILI.
Liver disease
Pre-existing hepatic dysfunction reduces reserve.
Alcohol use
Induces CYP enzymes, depletes glutathione → ↑ risk with hepatotoxins.
Malnutrition & obesity
Malnutrition: ↓ glutathione. Obesity: steatosis, NAFLD → sensitizes liver.
Polypharmacy
↑ drug interactions and cumulative hepatotoxicity risk.
Herbal/traditional meds
Often unregulated; hepatotoxic ingredients common (e.g. kava, green tea extract).
Paracetamol
Dose-dependent hepatotoxin → intrinsic DILI via NAPQI.
Amoxicillin-clavulanate
Common cause of idiosyncratic DILI.
Valproic acid
Valproic acid
Causes mitochondrial dysfunction.
Phenytoin, isoniazid
Immune-mediated idiosyncratic DILI.
Statins & methotrexate
Can cause liver enzyme elevations and long-term injury.
Herbal examples
Kava, green tea extract — commonly implicated in DILI cases.
Asymptomatic DILI
Detected via routine LFTs; ALT/AST elevations.
Non-specific symptoms
Fatigue, nausea, anorexia, RUQ discomfort.
Liver-specific signs
Jaundice, dark urine, pale stools, itching, RUQ tenderness, hepatomegaly.
Severe/fulminant liver failure
Coagulopathy (↑INR), encephalopathy, ascites, confusion.
Lab indicators of DILI
↑ALT/AST (hepatocellular), ↑ALP/GGT (cholestatic), ↑bilirubin, ↑INR.
Time to onset
Varies: days (e.g. paracetamol), weeks/months (idiosyncratic DILI).
DILI is a diagnosis of exclusion
Rule out viral hepatitis, alcohol use, autoimmune liver disease.
Causality assessment
Use RUCAM (Roussel-Uclaf Causality Assessment Method) score.
Detailed history
Assess timing of drug exposure, duration, dosage, other risk factors.
Management basics
Stop offending drug, monitor LFTs and symptoms, supportive care.
Specific antidotes
N-acetylcysteine (NAC) for paracetamol toxicity; others are supportive only.
Prevention strategies
Use lowest effective doses, monitor LFTs on hepatotoxic drugs (e.g. methotrexate), patient education, avoid polypharmacy and unsafe supplements.