Drug-Induced Liver Injury

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: $R = (ALT / ULN_{ALT}) / (ALP / ULN_{ALP})$

⭐ 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.

⭐ 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

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.

• 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.