What medications should be avoided in patients with elevated liver enzymes?

Medications to Avoid with Elevated Liver Enzymes

Patients with elevated liver enzymes should immediately stop or avoid acetaminophen, NSAIDs, known hepatotoxic drugs, and any unnecessary medications, while infliximab is absolutely contraindicated in immune-related hepatitis. 1, 2

Immediate Actions for Grade 2 or Higher Elevations (AST/ALT >3× ULN)

Stop all unnecessary medications and any known hepatotoxic drugs immediately. 1

• Temporarily hold other potentially hepatotoxic oncologic agents if the patient is receiving cancer treatment 1
• Advise against alcohol consumption and potentially hepatotoxic dietary supplements 1
• Rule out viral hepatitis, medication-induced injury, and other competing etiologies before attributing elevations to any single cause 1

Absolutely Contraindicated Medications

Infliximab

• Infliximab is absolutely contraindicated for immune-related hepatitis and should never be used in patients with hepatic immune-related adverse events 1

High-Priority Medications to Avoid or Minimize

Acetaminophen

• Acetaminophen is the most common cause of drug-induced acute liver failure (15% of all acute liver failure cases, up to 50% of fulminant hepatic failure) and should be avoided or strictly minimized in patients with any signs of liver dysfunction 2
• Avoid acetaminophen during acute hepatitis until resolution of the acute episode 1
• However, at recommended doses in stable chronic liver disease without acute hepatitis, acetaminophen can be used more safely than NSAIDs 3

NSAIDs

• NSAIDs should be avoided in patients with elevated liver enzymes due to hepatotoxicity risk 1, 2
• Avoid NSAIDs in patients with GFR <30 mL/min/1.73 m² and use caution with prolonged therapy when GFR <60 mL/min/1.73 m² 1
• NSAIDs carry additional risks of gastrointestinal toxicity, platelet impairment, and nephrotoxicity that are particularly problematic in liver disease 3, 4

Azole Antifungals

• Ketoconazole carries the highest risk among azoles with potential for severe hepatotoxicity regardless of dose or duration 2
• Avoid amphotericin unless no alternative exists when GFR <60 mL/min/1.73 m² 1
• Reduce maintenance dose of fluconazole by 50% when GFR <45 mL/min/1.73 m² 1

Medications Requiring Extreme Caution and Dose Reduction

Methotrexate

• Methotrexate increases risk of liver toxicity, particularly when combined with other hepatotoxic agents like acitretin 1
• Reduce methotrexate dose when GFR <60 mL/min/1.73 m² and avoid if possible when GFR <15 mL/min/1.73 m² 1
• Monitor liver enzymes closely; if enzymes exceed 5× normal, discontinue the drug 1
• Avoid methotrexate in patients at risk for hepatotoxicity including those with pre-existing liver disease 1

Antiretroviral Agents

• Lopinavir/ritonavir can cause moderate-to-severe aminotransferase elevations in 3-10% of patients 2
• Remdesivir causes hepatotoxicity with elevated hepatic enzymes in 23% of patients and requires liver function monitoring 2
• Multiple antiretroviral combinations require dose reduction of rosuvastatin to 5-10 mg once daily maximum 5

Statins

• Rosuvastatin is contraindicated in acute liver failure or decompensated cirrhosis 5
• Do not exceed rosuvastatin 5 mg once daily when used with cyclosporine 5
• Do not exceed rosuvastatin 10 mg once daily when used with teriflunomide, enasidenib, capmatinib, or certain antivirals 5
• Despite theoretical concerns, patients with elevated baseline liver enzymes do not have higher frequency of statin hepatotoxicity than those with normal enzymes in stable chronic liver disease 6

Immunosuppressants

• Cyclosporine requires dose reduction if creatinine increases >25% above baseline and monitoring for hepatotoxicity 1
• Azathioprine dosing may be guided by TPMT enzyme activity with monitoring for liver enzyme elevations 1
• Mycophenolate mofetil may be added for steroid-refractory hepatitis after infectious causes are ruled out 1

Medications Requiring Monitoring but Not Absolute Avoidance

Chemotherapeutic Agents

• Reduce cisplatin dose when GFR <60 mL/min/1.73 m² and avoid when GFR <30 mL/min/1.73 m² 1
• Reduce melphalan dose when GFR <60 mL/min/1.73 m² 1

Antimicrobials

• Tetracyclines can exacerbate uremia; reduce dose when GFR <45 mL/min/1.73 m² 1
• Reduce macrolide dose by 50% when GFR <30 mL/min/1.73 m² 1
• Aminoglycosides require dose reduction and serum level monitoring when GFR <60 mL/min/1.73 m² 1

Other Medications

• Valproic acid should be avoided or minimized in patients with vomiting and potential liver enzyme elevations 2
• Hydroxychloroquine can cause ALT elevation in <5% of patients and requires caution with hepatic disease 2
• Lithium is nephrotoxic and may cause renal tubular dysfunction; monitor GFR, electrolytes, and lithium levels every 6 months 1

Grading System for Management Decisions

Grade 1 (AST/ALT 1-3× ULN or bilirubin 1-1.5× ULN)

• Continue close monitoring with labs 1-2 times weekly 1
• Review and stop unnecessary medications 1
• No specific treatment required for Grade 1 elevations alone 1

Grade 2 (AST/ALT 3-5× ULN or bilirubin 1.5-3× ULN)

• Stop unnecessary medications and any known hepatotoxic drugs immediately 1
• Hold potentially hepatotoxic agents temporarily 1
• Consider 0.5-1 mg/kg/day oral prednisone if no improvement after 3-5 days 1

Grade 3-4 (AST/ALT >5× ULN or bilirubin >3× ULN)

• Discontinue potentially hepatotoxic agents permanently if symptomatic 1
• Start 1-2 mg/kg methylprednisolone immediately 1
• Consider liver biopsy if steroid-refractory to rule out alternative diagnoses 1

Critical Pitfalls to Avoid

• Do not rely solely on laboratory values; serum liver tests may not be abnormal in all instances of hepatotoxicity 2
• Instruct patients to stop medication immediately if abdominal pain, vomiting, jaundice, or hepatitis symptoms develop 2
• Do not assume all drugs are contraindicated; most medications can be used safely in stable chronic liver disease with appropriate monitoring 7, 8
• Distinguish between acute hepatitis and stable chronic liver disease; recommendations differ significantly between these two scenarios 3, 8
• Monitor for drug-drug interactions as patients with liver disease often require multiple medications 4, 8
• Check for alternative causes including viral hepatitis, alcohol use, biliary obstruction, hepatic metastases, and thromboembolic events before attributing elevations to medications 1