Understanding Drug-Induced Autoimmune Hepatitis (DIAIH)
Drug-induced autoimmune hepatitis (DIAIH) is a form of liver injury that clinically, biochemically, and histologically mimics classic autoimmune hepatitis (AIH) but is initiated by exposure to a medication [1.4.1, 1.4.2]. While idiosyncratic drug-induced liver injury (DILI) is rare, affecting an estimated 14 to 19 per 100,000 people annually, DIAIH represents a significant subset of these cases [1.6.2]. It is characterized by the presence of autoantibodies, a hepatocellular pattern of liver enzyme elevation, and liver biopsy findings showing interface hepatitis with plasma cell infiltration [1.4.1, 1.2.3]. The condition typically resolves after the offending medication is discontinued, which is a key difference from idiopathic AIH that often requires lifelong immunosuppression [1.2.3, 1.5.5].
Common Medications That Trigger Autoimmune Hepatitis
A wide range of medications has been implicated in triggering DIAIH. They are often categorized by the strength of their association (definite, probable, or possible) [1.2.2].
Definite Association
These drugs are classically and strongly associated with causing DIAIH.
- Minocycline: A tetracycline antibiotic frequently prescribed for acne, minocycline is one of the most well-documented causes of DIAIH [1.7.3]. The risk is particularly noted with long-term use, often for months or even years [1.7.1]. Studies show that minocycline and nitrofurantoin together accounted for 92% of DIAIH cases in one series [1.8.3].
- Nitrofurantoin: This antibiotic is commonly used to treat urinary tract infections (UTIs) [1.8.2]. Long-term prophylactic use increases the risk, especially in elderly women, but acute cases have been reported even after short courses of therapy [1.8.4, 1.8.2]. Along with minocycline, it has one of the highest reported risk odds ratios for DIAIH [1.6.3].
- Infliximab: A biologic tumor necrosis factor (TNF)-alpha inhibitor used for autoimmune conditions like Crohn's disease and rheumatoid arthritis, infliximab is an increasingly recognized cause of DIAIH [1.9.1, 1.9.2]. The onset is typically within a few months of starting treatment [1.9.1].
- Methyldopa and Hydralazine: Though used less commonly now, these older antihypertensive medications are classic examples of drugs that can induce an autoimmune-like hepatitis [1.2.3, 1.4.1].
Probable and Recent Associations
Newer medications and other commonly used drugs are also being identified as potential triggers.
- Statins: This widely prescribed class of cholesterol-lowering drugs, including atorvastatin, simvastatin, and rosuvastatin, has been linked to DIAIH [1.3.2, 1.10.1]. While the risk is considered rare, these drugs can trigger a persistent autoimmune hepatitis that may continue even after the drug is stopped [1.10.1, 1.10.2].
- Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): Drugs like diclofenac and meloxicam have a probable association with DIAIH [1.2.2, 1.3.2].
- Immune Checkpoint Inhibitors: Antitumor agents like nivolumab and pembrolizumab, used in cancer immunotherapy, have been identified as significant causes of DIAIH, often with a relatively short time to onset [1.3.2].
- Herbal and Dietary Supplements: There is growing evidence that some supplements can trigger autoimmune hepatitis. Turmeric has been documented in case reports to cause an AIH-like picture, which resolved upon discontinuation [1.11.1, 1.11.4]. Other supplements, such as green tea extract and black cohosh, have also been implicated in liver injury with autoimmune features [1.11.3].
Comparison of Classic vs. Drug-Induced Autoimmune Hepatitis
| Feature | Idiopathic (Classic) AIH | Drug-Induced AIH (DIAIH) |
|---|---|---|
| Trigger | Unknown, likely environmental factor in a genetically predisposed person [1.4.4]. | Specific medication or supplement [1.4.1]. |
| Onset | Often insidious and chronic, but can be acute [1.6.2]. | Typically acute or subacute, often within months of starting a drug [1.4.1, 1.2.3]. |
| Resolution | Usually requires long-term or lifelong immunosuppressive therapy [1.5.5]. | Typically resolves completely after withdrawal of the offending drug [1.2.3, 1.7.3]. |
| Relapse | Common upon withdrawal of therapy [1.5.5]. | Rare, unless the drug is reintroduced [1.7.3]. |
| Fibrosis/Cirrhosis | Can be present at diagnosis in up to one-third of patients [1.4.4]. | Advanced fibrosis or cirrhosis is less common, but possible with some drugs like nitrofurantoin [1.8.4, 1.6.2]. |
| Immuno-allergic Signs | Uncommon. | More common, with features like rash, fever, and eosinophilia in up to 30% of cases [1.6.2]. |
Diagnosis and Management
The diagnosis of DIAIH involves a thorough medication history, blood tests to check liver enzymes (ALT, AST) and autoantibodies (ANA, ASMA), and often a liver biopsy [1.4.1, 1.4.4]. The biopsy in DIAIH can be indistinguishable from classic AIH, showing interface hepatitis and plasma cell infiltrates [1.6.2].
The most critical step in management is to identify and promptly discontinue the suspected medication [1.5.4]. In many cases, liver enzymes will begin to normalize after stopping the drug. However, if the injury is severe or recovery is slow, a course of corticosteroids, such as prednisone, may be prescribed to suppress the immune response [1.5.1]. Unlike classic AIH, the steroid course for DIAIH is typically short, and the medication can often be tapered and discontinued within 3 to 6 months without relapse [1.5.1, 1.7.1].
Conclusion
Drug-induced autoimmune hepatitis is a serious but often reversible condition triggered by a variety of medications. Classic culprits like minocycline and nitrofurantoin remain significant causes, while newer agents like biologic drugs, statins, and even some herbal supplements are increasingly recognized triggers. Awareness of what medications trigger autoimmune hepatitis is essential for clinicians to ensure prompt diagnosis. The cornerstone of management is the withdrawal of the causative agent, which in most cases leads to a full recovery, distinguishing DIAIH from its idiopathic counterpart that requires chronic therapy.
For more information, a valuable resource is the LiverTox database from the National Institutes of Health.
