What medications can cause Drug-Induced Liver Injury (DILI)?

Medications That Cause Drug-Induced Liver Injury (DILI)

The most common causes of DILI include antibiotics (particularly amoxicillin/clavulanate), acetaminophen, NSAIDs, statins, isoniazid, herbal/dietary supplements, and increasingly, oncology drugs including immune checkpoint inhibitors. 1, 2, 3

High-Risk Medication Categories

Antibiotics

• Amoxicillin/clavulanate remains the predominant cause of cholestatic DILI and is among the most frequently implicated agents overall 1, 3
• Fluoroquinolones (e.g., ciprofloxacin) are recognized causes of DILI 3
• Nitrofurantoin and minocycline are leading causes of autoimmune-like DILI, particularly affecting women 4, 5
• Isoniazid is a well-established hepatotoxic agent, with increased risk when combined with other drugs like carbamazepine 2, 3, 6

Analgesics and Anti-Inflammatory Drugs

• Acetaminophen causes predictable, dose-dependent hepatotoxicity and is the most common cause of acute liver failure 4, 2
• NSAIDs are among the top three most common causes of idiosyncratic DILI 2, 3
• Diclofenac is repeatedly associated with autoimmune-feature DILI 5

Cardiovascular Medications

• Statins are common DILI culprits, though generally safe in patients with NAFLD, and can cause autoimmune-feature hepatotoxicity 4, 3, 5
• Hydralazine is a leading cause of autoimmune-like DILI 4, 5
• α-methyldopa causes autoimmune-feature liver injury 4, 5

Oncology Drugs

• Newly approved oncotherapeutic agents have been associated with the highest risk of DILI compared with other drug classes in recent years 4
• Traditional cytotoxic agents (cisplatin, doxorubicin) cause hepatotoxicity 4, 6
• Tyrosine kinase inhibitors are significant DILI causes 4, 3
• Immune checkpoint inhibitors cause immune-mediated liver injury (ILICI), which is partially predictable and responsive to corticosteroids 4, 7
• Antibody-drug conjugates are emerging DILI causes 4

Immunosuppressive and Biologic Agents

• Anti-TNF-α agents (e.g., infliximab, adalimumab) cause autoimmune-feature hepatotoxicity and cholestatic liver disease 4, 3, 5
• Methotrexate causes hepatotoxicity in approximately 10% of IBD patients, with fibrosis occurring in 8.5% of treated patients 4
• Azathioprine and 6-mercaptopurine cause hepatotoxicity in 3-15% of patients, with potential for veno-occlusive disease and nodular regenerative hyperplasia 4
• Thiopurines (including 6-thioguanine) can damage hepatic vascular endothelium 4

Neuropsychiatric Medications

• Carbamazepine requires baseline and periodic liver function monitoring due to potential liver damage 6
• Valproic acid interacts with multiple medications and requires monitoring when combined with other hepatotoxic agents 8, 6

Antimicrobials for Resistant Infections

• Colistin carries significant hepatotoxicity risk and should be discontinued first when managing DILI in patients on multiple antimicrobials 8
• Teicoplanin has moderate hepatotoxic potential 8
• Ceftazidime-avibactam carries moderate risk of transaminase elevations, particularly significant in patients with baseline liver dysfunction 8

Herbal and Dietary Supplements

• Herbal remedies are increasingly recognized as significant DILI causes 2, 3
• These agents should be specifically queried during history-taking as patients often do not volunteer this information 4

Pattern-Specific Considerations

Hepatocellular Pattern

• Most idiosyncratic DILI presents with hepatocellular injury (elevated ALT/AST predominance) 4
• Acetaminophen causes characteristic centrilobular necrosis 4, 9

Cholestatic Pattern

• Amoxicillin/clavulanate is the classic cholestatic DILI agent 1
• Antibiotics overall remain the predominant cause of cholestatic injury 1
• Anti-TNF-α agents can cause cholestatic liver disease 4

Autoimmune-Like Pattern

• Nitrofurantoin, minocycline, α-methyldopa, and hydralazine are the leading causative agents for autoimmune-like DILI, accounting for 2-17% of patients initially diagnosed with autoimmune hepatitis 4, 5
• Statins and anti-TNF-α agents are more recently recognized causes 5
• These cases show positive ANA (83%) and SMA (50%), elevated gamma globulin, and interface hepatitis with plasma cell infiltration 4

Critical Management Points

Risk Factors

• Medication dose, drug lipophilicity, and extent of hepatic metabolism increase DILI risk 3
• Older age is a risk factor for cholestatic DILI 1
• Patients with pre-existing chronic liver disease are not necessarily more prone to develop DILI, but face significantly higher risk for adverse outcomes including mortality when DILI occurs 4

Polypharmacy Considerations

• Multiple antimicrobial agents significantly increase DILI risk through drug interactions and cumulative hepatotoxicity 8
• Five or more concurrent medications substantially compound hepatotoxicity risk 8
• Carbamazepine increases isoniazid-induced hepatotoxicity when used concomitantly 6

Distinguishing Features

• AIH-like DILI improves within one month in most cases after drug discontinuation, whereas true autoimmune hepatitis recurs after stopping immunosuppression 4
• Latency period for autoimmune-like DILI varies from 1-8 weeks to 3-12 months 4
• Immune checkpoint inhibitor-related liver injury typically shows negative or low autoantibody levels and normal gamma globulin, distinguishing it from classic autoimmune-like DILI 4

Common Pitfalls

• Do not assume elevated liver enzymes in NASH patients are due to underlying disease—ALT ≥5× ULN or ≥3× baseline warrants DILI evaluation 4
• Patients may not volunteer use of herbal/dietary supplements unless specifically asked 4
• DILI can progress despite discontinuation of the offending drug, requiring continued vigilance 8
• Rechallenge should be avoided in cases meeting Hy's Law criteria (ALT ≥3× ULN with bilirubin ≥2× ULN without cholestasis) or showing hepatic decompensation 7