Drug-Induced Liver Injury

Drug induced liver injury is hepatic damage caused by a drug, herbal remedy or dietary supplement after other causes are excluded.

• Types: intrinsic (dose dependent, predictable, such as paracetamol) and idiosyncratic (unpredictable, immune or metabolic, such as amoxicillin-clavulanate, isoniazid, nevirapine).
• In Kenya, anti-tuberculosis drugs (isoniazid, rifampicin, pyrazinamide), antiretrovirals (nevirapine, efavirenz), cotrimoxazole, herbal medicines and traditional remedies, and paracetamol are leading causes.
• Risk factors: age, female sex, malnutrition, alcohol, HIV, chronic hepatitis B or C, polypharmacy and slow acetylator status.

Asymptomatic transaminase rise to jaundice, nausea, anorexia, right upper quadrant pain, dark urine, pruritus.

• Hypersensitivity features in some: fever, rash, eosinophilia, lymphadenopathy (drug reaction with eosinophilia and systemic symptoms), arthralgia.
• Latency of 5 days to 3 months after starting the drug (longer with herbal agents).
• Patterns by the ratio of ALT (times upper limit) to ALP (times upper limit): hepatocellular above 5, cholestatic below 2, mixed 2 to 5.
• Differential diagnosis: viral hepatitis (A, B, C, E), autoimmune hepatitis, alcohol-related liver disease, biliary obstruction, ischaemic hepatitis, Wilson disease, malaria, sepsis, congestive hepatopathy.
• Complications: acute liver failure (jaundice with hepatocellular injury carries 10 percent mortality or transplant), chronic liver injury, vanishing bile duct syndrome, cirrhosis, hepatic fibrosis and prolonged cholestasis.

Detailed drug, herbal, supplement and alcohol history with timeline; causality assessment is clinical.

• Liver profile (ALT, AST, ALP, bilirubin), INR, albumin, full blood count with eosinophils, creatinine.
• Exclude other causes: hepatitis A IgM, HBsAg and IgM anti-HBc, anti-HCV, HEV RNA, cytomegalovirus, Epstein-Barr virus, autoimmune markers (ANA, anti-smooth muscle antibody, IgG), ultrasound, ceruloplasmin if under 40 years, paracetamol level.
• Liver biopsy if autoimmune hepatitis is suspected or injury is persistent.

Supportive

• Stop the suspected drug and all non-essential hepatotoxic drugs; avoid rechallenge unless essential.
• Stop for ALT above 5 times the upper limit of normal (or above 3 times with symptoms or bilirubin above 2 times the upper limit).
• Admit for jaundice with INR above 1.5, encephalopathy or symptoms.

Pharmacological

• Acute liver failure of any cause: N-acetylcysteine (150 mg/kg over 1 hour, then 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours), lactulose 30 mL every 6 to 8 hours, transplant referral.
• Hypersensitivity or autoimmune-like injury: prednisolone 0.5 to 1 mg/kg daily (taper over 4 to 8 weeks).
• Cholestatic injury with pruritus: cholestyramine 4 g up to three times daily; ursodeoxycholic acid 13 to 15 mg/kg/day.
• Anti-tuberculosis therapy: stop all hepatotoxic drugs, use ethambutol plus a fluoroquinolone (levofloxacin 750 mg daily) plus an injectable (streptomycin 15 mg/kg daily) until ALT falls below 2 times the upper limit; then reintroduce rifampicin first (full dose, 3 to 7 days), then isoniazid, then pyrazinamide sequentially with ALT monitoring every 2 to 3 days; leave out the culprit.
• Antiretroviral injury: replace nevirapine with dolutegravir 50 mg daily or efavirenz 600 mg daily, with specialist advice.

Special groups: HIV and tuberculosis (specialist input), pregnancy (avoid sodium valproate and tetracyclines), children (dose by weight, withhold culprit).

Red flags: jaundice with hepatocellular injury, INR above 1.5, encephalopathy, rash with eosinophilia, rapidly rising bilirubin.

Follow-up: ALT and bilirubin weekly until improving then every 1 to 2 weeks; recheck at 6 months for chronic injury; record the drug as an allergy.