Hepatotoxic Medicine Review

Drug-induced liver injury is liver damage caused by a medicine, herbal product or supplement, presenting as hepatocellular, cholestatic or mixed injury. It is either intrinsic and dose-related, as with paracetamol, or idiosyncratic and largely unpredictable. A structured medicine review in every patient with abnormal liver tests identifies culprits, prevents re-exposure and guides safer substitution.

Pattern by R value. R equals (ALT divided by its upper limit of normal) divided by (alkaline phosphatase divided by its upper limit of normal). R of 5 or more is hepatocellular, 2 or less is cholestatic, and between 2 and 5 is mixed.

Hy’s law. ALT over 3 times the upper limit of normal plus bilirubin over 2 times the upper limit of normal, without another cause, carries about 10% mortality or transplant risk.

Timing. Most idiosyncratic injury appears 5 to 90 days after starting. Co-amoxiclav and flucloxacillin can present weeks after stopping.

Common culprits by pattern.

Risk factors. Older age, female sex, alcohol, malnutrition, HIV, chronic hepatitis B or C, slow acetylator status for isoniazid, and HLA types such as HLA-B*57:01 for flucloxacillin.

Safer alternatives. Replace co-amoxiclav with amoxicillin plus a non-hepatotoxic agent where cover allows. Replace nitrofurantoin long-term prophylaxis with trimethoprim or a non-antibiotic option. Replace valproate with levetiracetam where seizure type permits.

East Africa. Tuberculosis treatment and antiretroviral therapy are the leading drug causes. Herbal remedies are common and often not disclosed. Nevirapine is now rarely used but still found in older regimens.

First-line tuberculosis treatment doses. Rifampicin 10 mg/kg (maximum 600 mg), isoniazid 5 mg/kg (maximum 300 mg), pyrazinamide 25 mg/kg (maximum 2 g) and ethambutol 15 mg/kg, all orally once daily.

Tuberculosis liver injury. Stop rifampicin, isoniazid and pyrazinamide if ALT exceeds 3 times the upper limit of normal with symptoms or jaundice, or 5 times without symptoms. If the patient is unwell or disease is severe, give ethambutol plus levofloxacin until liver tests recover.

Reintroduction. When ALT is under 2 times the upper limit of normal, restart rifampicin at full dose. After 3 to 7 days with stable tests, add isoniazid. Omit pyrazinamide if the injury was severe and extend treatment to 9 months.

Isoniazid add-on. Give pyridoxine 10 to 25 mg orally daily to reduce neuropathy.

Non-paracetamol acute liver failure. In early encephalopathy (grade 1 to 2), give intravenous acetylcysteine 150 mg/kg over 1 hour, then 12.5 mg/kg/hour for 4 hours, then 6.25 mg/kg/hour for 67 hours.

Immune checkpoint inhibitor hepatitis. Grade 2 (ALT 3 to 5 times the upper limit of normal): hold the drug and repeat tests every 3 days. Grade 3 or more (ALT over 5 times): stop and give methylprednisolone 1 to 2 mg/kg intravenously daily, then taper oral prednisolone over at least 4 weeks.

Special groups. - Pregnancy: tuberculosis treatment continues with first-line drugs and pyridoxine; liver injury risk is higher postpartum. - Children: valproate is contraindicated in POLG mitochondrial disease, and risk is highest under 2 years. - HIV: dolutegravir carries lower liver risk than efavirenz or nevirapine. - Kidney impairment: in interim regimens, give ethambutol 15 to 25 mg/kg three times weekly when creatinine clearance is under 30 mL/min.

Baseline. ALT, AST, alkaline phosphatase, bilirubin and INR before hepatotoxic drugs, with hepatitis B, C and HIV status where relevant.

Monitoring intervals. - Tuberculosis treatment in pre-existing liver disease, HIV or alcohol use: liver tests every 2 weeks for 2 months, then monthly. - Methotrexate: every 2 to 4 weeks for 3 months, then every 3 months. - Amiodarone: every 6 months. - Statins: baseline and once at 3 months; then only if symptoms develop.

Stopping thresholds. ALT over 3 times the upper limit of normal with symptoms; ALT over 5 times without symptoms; ALT over 3 times plus bilirubin over 2 times; alkaline phosphatase over 2 times with rising bilirubin.

Re-challenge. Never re-challenge after Hy’s law injury, hypersensitivity features (rash, fever, eosinophilia), or autoimmune-like injury.

Referral and escalation. Refer urgently for INR over 1.5, encephalopathy or bilirubin rise. Report every suspected case to the national pharmacovigilance system.