Drug induced liver injury (DILI)

DRUG-INDUCED LIVER INJURY (DILI): A COMPREHENSIVE ESSAY

  1. Introduction
    Drug-induced liver injury (DILI) covers the structural or functional derangement of the liver that follows exposure to a pharmaceutical agent, herbal product, traditional remedy or nutritional supplement. Although relatively infrequent (≈10–19 cases/100 000 patient-years), DILI is the single commonest cause of acute liver failure (ALF) in the United States (mainly acetaminophen) and the leading reason that an approved drug is withdrawn from the market. Because it mimics virtually every other hepatobiliary disorder, high clinical vigilance and systematic evaluation are required for timely diagnosis and management.

  2. Classification
    A. Intrinsic (predictable) DILI
    • Dose-related, short latent period, reproducible in animals.
    • Prototypical agent: acetaminophen (>150 mg/kg or >7.5 g in adults).
    • Mechanism usually direct hepatocellular toxicity by reactive metabolites or mitochondrial dysfunction.

B. Idiosyncratic (unpredictable) DILI
• Occurs in susceptible individuals at therapeutic doses; latency days to months.
• Estimated incidence 1:10 000–1:100 000 prescriptions.
• Two major phenotypes: metabolic (toxic) and immune-allergic (hypersensitivity).

C. Indirect or secondary hepatotoxicity
• Drug triggers another condition that injures the liver (e.g., immune checkpoint inhibitor hepatitis, phosphatidylinositol-3-kinase δ inhibitors activating HBV).

  1. Epidemiology and High-Risk Agents
    Global registries (e.g., U.S. DILIN, Spanish DILI Registry, Latin-DILI Network) consistently identify:
    • Acetaminophen, isoniazid, rifampin/pyrazinamide, amoxicillin-clavulanate, flucloxacillin, nitrofurantoin, minocycline, diclofenac, valproic acid, antiepileptics, statins, allopurinol, methotrexate, Chinese/Kampo herbs, bodybuilding supplements (anabolic-androgenic steroids).
    • Herbal and dietary supplements now account for 15–20 % of DILI in Western cohorts and >30 % in Asia.

  2. Pathogenesis: Multiple Converging Mechanisms
    (i) Bioactivation to reactive metabolites (CYP-mediated) → covalent binding to proteins, lipid peroxidation, mitochondrial damage.
    (ii) Immune activation: drug or metabolite forms a neo-antigen that triggers HLA-restricted T-cell responses (flucloxacillin–HLA-B57:01; amoxicillin-clavulanate–HLA-A02:01, DRB1*15:01).
    (iii) Mitochondrial dysfunction: valproate (inhibits β-oxidation), fialuridine (mtDNA depletion).
    (iv) Bile salt export pump (BSEP) inhibition and cholestasis: bosentan, macrolides.
    (v) Oxidative/nitrosative stress and impaired antioxidant defences: isoniazid depletes glutathione, exacerbated by malnutrition or chronic alcohol.

Host risk factors
• Age >60 y (cholestatic pattern), female sex (nitrofurantoin, minocycline), pregnancy (propylthiouracil), underlying liver disease, obesity/NAFLD, chronic alcohol, malnutrition, rapid acetylator status (INH), specific HLA alleles, and concomitant CYP-inducing drugs.

Drug-related risk factors
• Daily dose ≥50 mg, extensive hepatic metabolism (>50 %), high lipophilicity, and formation of reactive metabolites (“rule of two”).

  1. Clinical and Biochemical Patterns
    Latency varies: hours (acetaminophen), 2–8 weeks (isoniazid), months-years (amiodarone).
    Patterns are defined by the R-ratio = (ALT ÷ ULN) ÷ (ALP ÷ ULN).
    • Hepatocellular (R ≥ 5): jaundice, fatigue, right-upper-quadrant pain; AST/ALT often >5× ULN; may progress to ALF.
    • Cholestatic (R ≤ 2): jaundice, pruritus; ALP and GGT predominate; more benign but can be prolonged.
    • Mixed (2 < R < 5).
    Special phenotypes: autoimmune-like hepatitis (minocycline, nitrofurantoin, anti-TNF agents), sinusoidal obstruction syndrome (pyrrolizidine-containing herbs, oxaliplatin), steatohepatitis (tamoxifen, methotrexate), phospholipidosis (amiodarone), microvesicular steatosis and acute liver failure (valproate, tetracycline high-dose IV).

  2. Diagnostic Approach
    Step 1: Careful history (drugs, supplements, over-the-counter products, alcohol, timing).
    Step 2: Exclude competing aetiologies—viral hepatitis (A–E, CMV, EBV), autoimmune hepatitis (ANA, SMA, IgG), metabolic diseases (Wilson, hemochromatosis), biliary obstruction (US/CT/MRCP), ischemic or Budd–Chiari.
    Step 3: Apply causality instruments if needed: RUCAM (updated 2022), DILIN structured expert opinion, Naranjo scale.
    Step 4: Quantify severity (ALT, bilirubin, INR, encephalopathy). Hy’s law: hepatocellular injury with jaundice has 10 % mortality/transplant risk.
    Step 5: Consider liver biopsy when diagnosis unclear, autoimmune overlap suspected, or persistent cholestasis (>6 mo).

  3. Specific Biomarkers and Emerging Tools
    • Serum acetaminophen-cysteine adducts (APAP-CYS) confirm intrinsic overdose >24 h post-ingestion.
    • Cytokeratin-18 fragments, HMGB1 acetylated isoforms, microRNA-122 differentiate necrosis from apoptosis and predict outcome.
    • Genetic markers: HLA-B57:01 (flucloxacillin/DILI), HLA-A33:01 (cholestatic DILI in Asians).
    • In silico models (DILIsym) and 3-D organoids to identify high-risk compounds earlier in drug development.

  4. Management
    General principles

  5. Prompt discontinuation of the suspected agent—often the only required intervention.
  6. Supportive care; monitor ALT, bilirubin, INR every 24–72 h until clear decline.
  7. Hospitalise if INR >1.5, bilirubin >5 mg/dL, encephalopathy, rising creatinine, or pregnancy.

Specific measures
• Acetaminophen: N-acetylcysteine (NAC) 150 mg/kg bolus over 60 min → 50 mg/kg over 4 h → 100 mg/kg over 16 h (IV) or 140 mg/kg oral loading then 70 mg/kg q4 h × 17. NAC improves transplant-free survival even when used late in non-APAP ALF.
• Antitubercular therapy: in symptomatic hepatitis or ALT > 5× ULN (asymptomatic) or >3× ULN + symptoms, stop all drugs, exclude other causes, re-introduce sequentially (rifampin → isoniazid → pyrazinamide) once LFTs <2× ULN.
• Immune-checkpoint inhibitor hepatitis, minocycline/nitrofurantoin autoimmune-like DILI: prednisone 0.5–1 mg/kg/day taper.
• Cholestatic pruritus: cholestyramine, rifampin, bezafibrate, or ursodeoxycholic acid (limited evidence).
• Acute liver failure: manage in transplant centre; NAC infusion, treat cerebral oedema, infection prophylaxis, consider listing for transplantation (King’s College criteria).

  1. Outcomes and Prognosis
    • Majority (>90 %) of idiosyncratic cases resolve within 6 months.
    • Chronic DILI (LFTs abnormal ≥1 year) occurs in 5–20 %—risk factors: cholestatic pattern, older age, ductopenia (“vanishing bile-duct syndrome”), methotrexate-linked fibrosis.
    • Mortality/transplant rate: overall 9–12 %; reaches 30–40 % in idiosyncratic ALF.
    • Predictors of poor outcome: bilirubin >10 mg/dL, INR >1.5, encephalopathy, Hy’s law, serum K18 >1700 U/L.

  2. Prevention and Risk-Mitigation
    • Drug development: include high-content screening, mitochondrial assays, BSEP inhibition panels, pharmacogenomic stratification.
    • Regulatory guidance (FDA, EMA) mandates rigorous LFT monitoring and stopping rules in clinical trials (ALT ≥3× ULN + bilirubin ≥2× ULN).
    • Clinical practice: counsel on maximum daily doses of acetaminophen (≤3 g in adults), avoid concomitant alcohol, baseline and serial LFTs with high-risk drugs (isoniazid, methotrexate, immune checkpoint inhibitors), HLA-B*57:01 screening when flucloxacillin presumed necessary (cost-effectiveness debated).

  3. Future Directions
    • Qualified biomarker panels (miR-122, glutamate dehydrogenase, macrophage colony-stimulating factor receptor) for early detection and prognostication.
    • iPSC-derived hepatic organoids and microfluidic “liver-on-a-chip” platforms for personalised risk prediction.
    • Systems pharmacology models integrating host genetics, microbiome, and concomitant medications to forecast susceptibility.
    • Real-world big-data pharmacovigilance (FDA FAERS, WHO VigiBase) coupled with machine learning for near-real-time signal detection.

  4. Conclusion
    DILI remains a challenging, often elusive diagnosis whose clinical repercussions range from trivial aminotransferase bumps to fulminant hepatic failure. Early recognition, judicious drug cessation, and timely supportive or antidotal therapy can be lifesaving. Advances in mechanistic understanding, biomarker discovery, and predictive modelling promise more effective prevention and safer therapeutics in the future.

Suggested Harrison’s Principles of Internal Medicine Reading (21st edition, McGraw-Hill, 2022)
• Chapter 366 Drug- and Toxin-Induced Liver Disease
• Chapter 361 Approach to the Patient with Liver Disease
• Chapter 362 Evaluation of Abnormal Liver Chemistry Tests
• Chapter 368 Cirrhosis and Its Complications
• Chapter 79 Principles of Clinical Pharmacology (for dose-exposure‐toxicity relationships)

(For 20th edition users: Drug-Induced Liver Disease is Chapter 360; other chapter numbers shift accordingly.)