drug-induced hepatitis

**Definition and diagnosis:** DILI is a diagnosis of exclusion. Typical criteria: ALT >5x ULN, or ALP >2x ULN, or ALT >3x ULN with bilirubin >2x ULN, with a compatible temporal relationship to the drug. Exclude viral hepatitis (HAV, HBV, HCV, HEV), autoimmune hepatitis, alcohol, ischemia, biliary obstruction, and Wilson disease. Improvement after drug withdrawal (dechallenge) supports the diagnosis. The R ratio = (ALT/ULN) ÷ (ALP/ULN) classifies the pattern: R ≥5 hepatocellular, R ≤2 cholestatic, and 2–5 mixed.

**Mechanisms:** 1. **Intrinsic (dose-dependent, predictable):** Acetaminophen is the classic example. At toxic doses, glucuronidation and sulfation pathways saturate. CYP2E1 then produces NAPQI, and glutathione depletion leads to centrilobular (zone 3) necrosis. Other examples: amiodarone, methotrexate, niacin, and *Amanita phalloides* (a toxin rather than a drug). 2. **Idiosyncratic (dose-independent, unpredictable):** Immune-mediated (hypersensitivity) or metabolic. Hypersensitivity features include fever, rash, and eosinophilia, as with phenytoin, sulfonamides, and allopurinol. Metabolic idiosyncrasy is seen with isoniazid (slow acetylators), valproate, and halothane. Amoxicillin-clavulanate is the most common cause of idiosyncratic DILI in the West. HLA associations exist (e.g., HLA-B*57:01 with flucloxacillin).

**Patterns and key drug associations (high-yield):** - **Hepatocellular (↑↑ AST/ALT):** acetaminophen, isoniazid, rifampin, pyrazinamide, halothane, valproate, ketoconazole, statins (mild), methyldopa, nevirapine, and amiodarone. - **Cholestatic (↑↑ ALP, ↑ bilirubin):** anabolic steroids, oral contraceptives/estrogens, erythromycin and macrolides, chlorpromazine, amoxicillin-clavulanate, and ceftriaxone (biliary sludge). - **Mixed:** phenytoin, carbamazepine, sulfonamides, and captopril. - **Steatosis/microvesicular:** valproate, tetracyclines, amiodarone, and nucleoside reverse transcriptase inhibitors (NRTIs, via mitochondrial toxicity). - **Granulomatous hepatitis:** allopurinol, quinidine, hydralazine, and sulfonamides. - **Vascular injury:** oral contraceptives (Budd-Chiari), and sinusoidal obstruction syndrome from pyrrolizidine alkaloids and chemotherapy (e.g., busulfan, cyclophosphamide). - **Tumors:** oral contraceptives and anabolic steroids are linked to hepatic adenoma. Vinyl chloride is linked to angiosarcoma. - **Autoimmune-like DILI:** nitrofurantoin, minocycline, methyldopa, and hydralazine. - **Chronic or fibrosis:** methotrexate (fibrosis and cirrhosis) and vitamin A excess (stellate cell hyperplasia).

**Clinical presentation:** Often asymptomatic with incidentally elevated enzymes. Symptomatic patients have fatigue, nausea, RUQ pain, jaundice, dark urine, and pruritus (cholestatic). Hypersensitivity features suggest an immune-mediated cause. **Hy's law:** hepatocellular injury with jaundice (ALT >3x ULN plus bilirubin >2x ULN, without significant ALP elevation) carries about 10% mortality and predicts a risk of acute liver failure. Acute liver failure is marked by encephalopathy and INR >1.5.

**Management:** - Stop the offending drug immediately. This is the most important step. - **Acetaminophen overdose:** N-acetylcysteine (NAC) replenishes glutathione. Use the Rumack-Matthew nomogram (4–24 h after a single acute ingestion) to guide treatment. NAC is most effective within 8 h, but it should still be given if presentation is late or the time of ingestion is unknown. - Supportive care. Corticosteroids may be used for hypersensitivity or autoimmune-like DILI. Ursodiol or cholestyramine may be used for pruritus in cholestatic cases. - Liver transplant evaluation for acute liver failure (King's College criteria). - **Isoniazid:** monitor LFTs, and give pyridoxine (B6) to prevent neuropathy. Stop therapy if ALT >3x ULN with symptoms or >5x ULN without symptoms. - Avoid rechallenge with drugs that caused severe or hypersensitivity-type injury.

**Risk factors:** Older age, chronic alcohol use (induces CYP2E1 and depletes glutathione), malnutrition or fasting, preexisting liver disease, polypharmacy, and CYP inducers such as rifampin, phenytoin, and phenobarbital. Female sex is a risk factor for some idiosyncratic reactions (e.g., halothane, nitrofurantoin). Children are at risk with valproate.

**Board pearls:** - AST:ALT >2:1 suggests alcoholic hepatitis, whereas very high ALT/AST (>1000) suggests acetaminophen, ischemia, or viral hepatitis. - Halothane hepatitis presents with fever and jaundice days after exposure, with a risk of repeat exposure. - Amiodarone can cause both acute injury and a chronic phospholipidosis, with Mallory bodies on biopsy. - Isoniazid hepatotoxicity is higher in slow acetylators and in alcohol users. - Remember to ask about herbal and dietary supplements (green tea extract, kava, and bodybuilding supplements are common causes).