Drugs Commonly Implicated in Drug-Induced Liver Injury (DILI)
The most commonly implicated drugs in DILI are antibiotics (particularly amoxicillin-clavulanate), followed by cardiovascular agents, NSAIDs, and antineoplastic/immunomodulating agents, with significant geographic variation between Eastern and Western populations. 1, 2, 3
Most Frequently Implicated Drug Classes
In Western Populations
The highest-risk medications based on recent prospective registries include:
Antibiotics (34.9% of cases):
- Amoxicillin-clavulanate - the single most common cause globally, with incidence of approximately 1:2,300 new prescriptions 4, 5, 6
- Flucloxacillin - second most common antibiotic 2, 5
- Minocycline - high risk at approximately 1:1,000-2,400 prescriptions 1, 4
- Nitrofurantoin - approximately 1:1,000-2,400 prescriptions 1, 4
- Lower risk: clindamycin, doxycycline, azithromycin, amoxicillin (1:40,000-170,000) 4
Cardiovascular Agents (17.3% of cases):
- Statins - atorvastatin most common (1:10,000-50,000 prescriptions), followed by simvastatin 4, 2, 5
- Notably, β-blockers, thiazide diuretics, ACE inhibitors, and ARBs have very low DILI incidence 4
NSAIDs (12.5% of cases):
- Diclofenac - most commonly implicated NSAID with HLA-B*35:03 genetic association 1, 5, 7
- Ibuprofen, nimesulide also frequently reported 3, 5
Antineoplastic/Immunomodulating Agents (27% in recent European data):
- Anti-TNF agents - infliximab and adalimumab 1, 2
- Immune checkpoint inhibitors - nivolumab/ipilimumab 2
- Azathioprine - highest estimated incidence at 1:349-2,329 prescriptions 4, 6
In Eastern Populations
The pattern differs significantly 3:
- Anti-tuberculosis drugs (26.6%) - isoniazid-rifampicin-pyrazinamide combination most common
- Herbal and alternative medications (25.3%)
- Antibiotics (15.7%) - lower proportion than Western populations
Drugs Causing Autoimmune-Like Hepatitis
A specific subset of DILI presents as drug-induced autoimmune-like hepatitis (DI-AILH), accounting for 3-37% of DILI cases in registries. 1 The best-established causative agents are:
- Nitrofurantoin
- Minocycline
- Methyldopa
- Hydralazine
- Anti-TNF agents (mainly infliximab, also adalimumab)
- Statins (particularly atorvastatin) - unique in that 7/24 cases relapsed after steroid withdrawal 1
- Interferons, imatinib, diclofenac, methylprednisolone
- Herbal products: khat and tinospora cordifolia 1
Antiepileptic Drugs
Older antiepileptics carry high DILI risk (1:349-2,329 prescriptions), with carbamazepine and phenytoin frequently implicated 4, 2, 5
Critical Clinical Considerations
Timing matters: Most idiosyncratic DILI occurs within the first 6 months of drug initiation; medications used continuously for >1-2 years are unlikely to cause de novo liver injury 8. However, DI-AILH often has longer latency than typical DILI (commonly exceeding 3 months) 1.
Re-exposure is hazardous: Never re-challenge with the initially implicated drug if alternatives exist, as this can be dangerous 1.
Herbal and dietary supplements: These account for 15-25% of DILI cases in Western populations and warrant specific inquiry during history-taking 8, 2, 9.
Patients with chronic liver disease: While not necessarily more susceptible to DILI, they experience significantly worse outcomes including higher mortality when DILI occurs 10, 11.
Medications With Very Low DILI Risk
Despite millions of prescriptions, the following have fewer than 5 reported cases in major registries, indicating extremely low hepatotoxicity risk 4:
- Selective serotonin reuptake inhibitors (SSRIs)
- Metformin
- Most β-blockers
- Thiazide diuretics
- ACE inhibitors
- Angiotensin receptor blockers