Understanding Drug-Induced Liver Injury (DILI)
Drug-induced liver injury (DILI) is a condition where medications, including prescription, over-the-counter (OTC) drugs, or even herbal supplements, cause harm to the liver [1.4.3]. The liver's primary role includes metabolizing these substances, but sometimes this process can create toxic byproducts that lead to inflammation and cellular damage [1.7.5]. DILI is a significant concern, accounting for about 10% of all cases of acute hepatitis and is a leading reason for withdrawing medications from the market [1.3.6]. The estimated annual incidence of DILI is between 14 and 19 cases per 100,000 people in Western populations [1.3.3, 1.3.7].
Intrinsic vs. Idiosyncratic DILI
DILI is broadly categorized into two types:
- Intrinsic DILI: This type is predictable and dose-dependent. The most well-known example is liver damage from an acetaminophen overdose [1.4.3, 1.3.7].
- Idiosyncratic DILI: This form is unpredictable and not clearly related to the dose, affecting only susceptible individuals [1.3.7]. It can occur with a wide range of medications, often without warning. Antibiotics are the most common cause of idiosyncratic DILI, responsible for about 45% of cases [1.4.3].
Acetaminophen: The Medication Most Likely to Cause Liver Failure
While many drugs can harm the liver, taking too much acetaminophen (found in Tylenol and many other products) is the single most common cause of acute liver failure in the United States [1.2.4]. Acetaminophen toxicity is responsible for around 56,000 emergency department visits, 2,600 hospitalizations, and 500 deaths in the U.S. each year [1.2.7]. Alarmingly, about half of these overdoses are unintentional [1.2.7].
How Acetaminophen Damages the Liver
When taken at recommended doses, acetaminophen is safe. The liver metabolizes most of it through safe pathways [1.7.3]. However, a small portion is converted by cytochrome P-450 enzymes into a toxic byproduct called N-acetyl-p-benzoquinone imine (NAPQI) [1.7.1, 1.7.5]. Normally, a substance in the liver called glutathione quickly neutralizes NAPQI [1.7.5]. In an overdose, the main metabolic pathways become saturated, and more NAPQI is produced than the liver's glutathione supply can handle. The excess NAPQI builds up and binds to liver cells, causing oxidative injury, mitochondrial damage, and ultimately, widespread liver cell death (hepatocellular necrosis) [1.7.1, 1.7.3].
Other Medications with High Risk of Liver Damage
Beyond acetaminophen, several other medications and classes of drugs are frequently implicated in DILI. In studies of idiosyncratic (unpredictable) DILI, the antibiotic amoxicillin/clavulanate (Augmentin) is often cited as the most common individual cause [1.2.1, 1.3.1].
Other notable drugs and drug classes include:
- Antibiotics: Isoniazid (used for tuberculosis), nitrofurantoin, and sulfa drugs like trimethoprim-sulfamethoxazole are common culprits [1.2.1, 1.4.3].
- Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Medications like ibuprofen, naproxen, and diclofenac can cause liver injury [1.2.5, 1.6.3].
- Anticonvulsants: Drugs such as phenytoin, carbamazepine, and valproic acid carry a risk of hepatotoxicity [1.4.3].
- Statins: While generally considered safe with a low incidence of liver issues, these cholesterol-lowering drugs can cause liver test abnormalities [1.2.2, 1.4.4].
- Herbal and Dietary Supplements: These are an increasing cause of DILI, rising from 7% to 20% of cases in one study network over a decade [1.2.3]. Green tea extract, anabolic steroids, and various weight loss supplements are known offenders [1.2.3, 1.4.3].
Comparison of Common Hepatotoxic Drugs
| Medication/Class | Type of Injury | Commonality | Key Risk Factors |
|---|---|---|---|
| Acetaminophen | Intrinsic (Dose-dependent) | Most common cause of acute liver failure in the U.S. [1.2.4] | Exceeding the maximum recommended dose (3,000-4,000 mg/day for adults), chronic alcohol use, poor nutrition [1.2.2, 1.2.7]. |
| Amoxicillin/Clavulanate | Idiosyncratic | Most common cause of idiosyncratic DILI in many Western countries [1.3.1, 1.3.3]. | Older age, male gender [1.3.3]. |
| Isoniazid | Idiosyncratic | A leading cause in U.S. registries [1.2.1]. | Older age [1.3.3]. |
| NSAIDs (e.g., Ibuprofen) | Idiosyncratic | Common cause of DILI [1.2.1, 1.2.5]. | Varies by specific drug. |
| Herbal/Dietary Supplements | Idiosyncratic | A rapidly growing cause, accounting for up to 20% of DILI cases [1.2.3, 1.3.3]. | Lack of regulation, unknown ingredients, multi-ingredient products [1.2.3]. |
Recognizing and Preventing Liver Damage
Recognizing the signs of DILI early is critical. Unfortunately, significant damage can occur before symptoms become obvious [1.2.2].
Symptoms of Liver Damage
- Fatigue and a general feeling of being unwell [1.5.1]
- Nausea and vomiting [1.5.2]
- Pain in the upper right abdomen [1.5.3]
- Dark or tea-colored urine [1.5.4]
- Jaundice (yellowing of the skin and eyes) [1.5.1]
- Itching [1.5.3]
- Loss of appetite [1.5.2]
Prevention Strategies
- Adhere to Dosages: Never exceed the recommended dose of any medication, especially OTC products containing acetaminophen [1.6.3]. The maximum daily dose for acetaminophen is generally considered 3,000-4,000 mg [1.2.2, 1.2.6].
- Read Labels: Be aware that acetaminophen is an ingredient in hundreds of combination products for pain, colds, and flu [1.2.2].
- Limit Alcohol: Regular alcohol consumption increases the risk of liver damage from acetaminophen [1.2.2, 1.6.3].
- Inform Your Doctor: Keep your healthcare providers updated on all medications you take, including prescriptions, OTC drugs, and all supplements [1.6.2].
- Be Cautious with Supplements: Discuss any herbal or dietary supplements with your doctor before starting them, as they are not regulated like prescription drugs and can cause significant harm [1.6.6].
Conclusion
While many substances can potentially harm the liver, acetaminophen stands out as the medication most likely to cause acute liver failure, primarily due to overdose [1.2.4]. Following acetaminophen, the antibiotic amoxicillin/clavulanate is a leading cause of idiosyncratic drug-induced liver injury [1.2.1]. Patient education on proper dosing, awareness of combination products, and open communication with healthcare providers about all ingested substances—including supplements—are the cornerstones of preventing DILI. For further, detailed information on specific drugs, the LiverTox database from the National Institutes of Health is an authoritative resource [1.8.3, 1.8.5].
