OIA2004 DRUG INDUCED LIVER INJURY (DILI)

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40 Terms

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Drug-Induced Liver Injury (DILI)

Liver damage caused by prescription/OTC drugs, herbs, or supplements.

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Liver functions relevant to DILI

Drug metabolism (Phase I & II), detoxification, bile production, protein synthesis (e.g. albumin, clotting factors).

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First-pass effect

High exposure of liver to orally-administered drugs → increased susceptibility to injury.

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Intrinsic DILI

Predictable, dose-dependent (e.g. paracetamol overdose).

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Idiosyncratic DILI

Unpredictable, not dose-related (e.g. isoniazid, amoxicillin-clavulanate).

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Direct hepatocellular toxicity

Drug or metabolite directly damages hepatocytes (e.g. paracetamol via NAPQI accumulation).

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NAPQI (N-acetyl-p-benzoquinone imine)

Toxic metabolite of paracetamol; normally detoxified by glutathione.

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Glutathione depletion

Leads to NAPQI accumulation → binds proteins → hepatocyte death → centrilobular necrosis.

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Immune-mediated liver damage

Drug/metabolite forms hapten → activates immune cells → inflammation ± autoimmune reaction.

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Drugs causing immune-mediated DILI

Isoniazid, phenytoin, carbamazepine, antibiotics.

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Immune-mediated features

Fever, rash, eosinophilia, not dose-related.

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Mitochondrial dysfunction

Drugs impair ATP production or increase ROS → steatosis, necrosis.

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Drugs causing mitochondrial DILI

Valproate, tetracyclines, antiretrovirals (e.g. didanosine).

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Microvesicular steatosis

Small fat droplets in hepatocytes due to mitochondrial dysfunction.

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Genetic predisposition

CYP450 polymorphisms, HLA-B*5701 (flucloxacillin DILI risk).

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Age extremes

Elderly: polypharmacy + reduced hepatic reserve.

Neonates: immature enzyme systems.

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Sex-based risk

Females may have higher risk of immune-mediated DILI.

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Liver disease

Pre-existing hepatic dysfunction reduces reserve.

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Alcohol use

Induces CYP enzymes, depletes glutathione → ↑ risk with hepatotoxins.

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Malnutrition & obesity

Malnutrition: ↓ glutathione. Obesity: steatosis, NAFLD → sensitizes liver.

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Polypharmacy

↑ drug interactions and cumulative hepatotoxicity risk.

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Herbal/traditional meds

Often unregulated; hepatotoxic ingredients common (e.g. kava, green tea extract).

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Paracetamol

Dose-dependent hepatotoxin → intrinsic DILI via NAPQI.

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Amoxicillin-clavulanate

Common cause of idiosyncratic DILI.

Valproic acid

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Valproic acid

Causes mitochondrial dysfunction.

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Phenytoin, isoniazid

Immune-mediated idiosyncratic DILI.

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Statins & methotrexate

Can cause liver enzyme elevations and long-term injury.

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Herbal examples

Kava, green tea extract — commonly implicated in DILI cases.

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Asymptomatic DILI

Detected via routine LFTs; ALT/AST elevations.

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Non-specific symptoms

Fatigue, nausea, anorexia, RUQ discomfort.

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Liver-specific signs

Jaundice, dark urine, pale stools, itching, RUQ tenderness, hepatomegaly.

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Severe/fulminant liver failure

Coagulopathy (↑INR), encephalopathy, ascites, confusion.

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Lab indicators of DILI

↑ALT/AST (hepatocellular), ↑ALP/GGT (cholestatic), ↑bilirubin, ↑INR.

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Time to onset

Varies: days (e.g. paracetamol), weeks/months (idiosyncratic DILI).

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DILI is a diagnosis of exclusion

Rule out viral hepatitis, alcohol use, autoimmune liver disease.

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Causality assessment

Use RUCAM (Roussel-Uclaf Causality Assessment Method) score.

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Detailed history

Assess timing of drug exposure, duration, dosage, other risk factors.

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Management basics

Stop offending drug, monitor LFTs and symptoms, supportive care.

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Specific antidotes

N-acetylcysteine (NAC) for paracetamol toxicity; others are supportive only.

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Prevention strategies

Use lowest effective doses, monitor LFTs on hepatotoxic drugs (e.g. methotrexate), patient education, avoid polypharmacy and unsafe supplements.