Drug-Induced Liver Injury

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DILI Basics - Liver's Drug Drama

  • What is DILI? Liver injury caused by medications, herbal products, or toxins. Significant cause of Acute Liver Failure (ALF).
  • Key Injury Patterns:
    • Hepatocellular: Predominant Alanine Aminotransferase (ALT) elevation.
    • Cholestatic: Predominant Alkaline Phosphatase (ALP) elevation.
    • Mixed: Both ALT and ALP are elevated.
  • R-Value (CIOMS Scale): Quantifies liver injury pattern.
    • Formula: $R = (ALT / ULN_{ALT}) / (ALP / ULN_{ALP})$

DILI diagnostic algorithm

⭐ The R-value (CIOMS scale) is critical: Hepatocellular DILI is defined by $R \ge \textbf{5}$, Cholestatic DILI by $R \le \textbf{2}$, and Mixed DILI by $\textbf{2} < R < \textbf{5}$.

Mechanisms & Risks - Why Livers Suffer

  • Mechanisms of Injury:
    • Direct (Intrinsic): Predictable, dose-dependent. E.g., Paracetamol (NAPQI formation).
      • Pathways: Covalent binding, oxidative stress, mitochondrial dysfunction.
    • Idiosyncratic (iDILI): Unpredictable, not strictly dose-related.
      • Immune-allergic (e.g., halothane, phenytoin).
      • Non-allergic/Metabolic (e.g., isoniazid, valproate causing mitochondrial injury).
      • Bile salt export pump (BSEP) inhibition.
  • Key Risk Factors:
    • Drug: High daily dose (>50-100 mg/day), lipophilicity, extensive hepatic metabolism.
    • Host: Age (elderly ↑risk), genetics (e.g., CYP variants, HLA-B*5701), alcohol use, female sex, obesity, pre-existing liver disease, malnutrition. DILI Pathogenic Mechanisms Diagram

⭐ Most DILI cases are idiosyncratic, meaning they are unpredictable, not strictly dose-dependent, and occur in a minority of individuals exposed to the drug.

Top Drug Offenders - Pharma's Hit List

DrugPattern of InjuryKey Points / Management
ParacetamolIntrinsic, hepatocellular necrosisDose-dependent; Toxic dose >150 mg/kg; Antidote: NAC
Isoniazid (INH)Idiosyncratic, hepatocellular↑ risk with age, alcohol, rifampicin; Monitor LFTs
Valproic AcidIdiosyncratic, microvesicular steatosisReye-like syndrome; Carnitine may help
AmiodaroneIdiosyncratic, phospholipidosisMimics alcoholic hepatitis; Long half-life
StatinsIdiosyncratic, hepatocellular/cholestaticUsually mild ALT ↑; Monitor LFTs if symptomatic
NSAIDsIdiosyncratic, variedDiclofenac, Sulindac common; Discontinue drug
Amoxicillin-ClavulanateIdiosyncratic, cholestaticOften delayed onset (1-6 weeks); Jaundice common

Spotting & Solving - DILI Detective Work

⭐ Hy's Law identifies patients with hepatocellular DILI at high risk (10-50%) of fatal liver injury: Jaundice (Bilirubin >2-3x ULN) + ALT/AST elevation (>3x ULN) without significant ALP rise, in absence of other causes.

Mechanisms of Drug-Induced Liver Injury

  • Diagnosis:
    • Thorough drug history (timing, dose, prior exposure).
    • Exclude other liver diseases (viral, alcohol, autoimmune).
    • Causality assessment (e.g., RUCAM score).
    • Liver biopsy if diagnosis remains uncertain.
  • Management Principles:
    • Prompt withdrawal of suspected drug.
    • Supportive care; specific antidotes (e.g., NAC for paracetamol).
    • Monitor LFTs; consider transplant for ALF.

High‑Yield Points - ⚡ Biggest Takeaways

  • Paracetamol is the most common DILI cause; N-acetylcysteine is the antidote.
  • Intrinsic DILI is dose-dependent (e.g., paracetamol); Idiosyncratic DILI is unpredictable.
  • Amoxicillin-clavulanate and anabolic steroids frequently cause cholestatic DILI.
  • Isoniazid, halothane, and statins are common causes of hepatocellular DILI.
  • Reye's syndrome: aspirin in children with viral illness, causing encephalopathy and fatty liver.
  • Valproate can cause fatal hepatotoxicity, especially microvesicular steatosis in children.
  • Methotrexate use can lead to chronic liver injury, fibrosis, and cirrhosis.
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Drug of choice in paracetamol overdose:

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Drug of choice in paracetamol overdose:

N-acetylcysteine

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