Drug-Induced Liver Injury (DILI)

How medicines damage the liver

The liver processes most medicines, sometimes producing reactive by-products. Damage happens in two main ways:

• Intrinsic (predictable) injury: occurs with high enough doses in anyone. The classic example is acetaminophen: in overdose, a toxic by-product (NAPQI) overwhelms the liver's protective glutathione and kills liver cells. Injury typically appears within days.
• Idiosyncratic (unpredictable) injury: occurs in a small number of people at normal doses, due to individual immune or metabolic responses. It usually appears 5 to 90 days after starting the drug, but can be later. Genetics (such as certain HLA types) play a role.

Patterns of liver injury

Common causes

Medicines

• acetaminophen (paracetamol) in overdose, or at high regular doses with heavy alcohol use or fasting
• antibiotics: amoxicillin-clavulanate (the most common cause of idiosyncratic DILI in Western countries), nitrofurantoin, minocycline, fluoroquinolones, TB medicines (isoniazid, rifampin, pyrazinamide)
• anti-seizure drugs: valproate, phenytoin, carbamazepine
• methotrexate, azathioprine and some cancer drugs, including immune checkpoint inhibitors
• statins: mild enzyme rises are common, but serious injury is rare
• some antifungals and HIV medicines

Herbal and dietary supplements

Supplements are a growing cause of DILI. Products linked to liver injury include green tea extract, anabolic steroids in bodybuilding products, turmeric (in some cases), kava, ashwagandha, garcinia and multi-ingredient weight-loss supplements. They are not regulated as strictly as medicines, and labels may not reflect contents.

Risk factors

• older age (some drugs) or childhood (valproate, aspirin)
• female sex for some reactions
• heavy alcohol use
• existing liver disease
• taking multiple medicines
• genetic factors

Symptoms

Many people have no symptoms, and injury is found on blood tests. When present:

• tiredness, nausea and loss of appetite
• discomfort under the right ribs
• dark urine and pale stools
• jaundice: yellow skin and eyes
• itching, especially in the cholestatic pattern
• rash, fever and swollen glands in allergic-type reactions

Signs of liver failure include confusion, drowsiness, easy bleeding and bruising, and fluid in the belly.

Diagnosis

DILI is a diagnosis of exclusion, so doctors rule out other causes:

• Detailed medication history: every prescription, over-the-counter medicine, herbal product and supplement in the past 6 months, with start and stop dates
• Liver blood tests: ALT, AST, alkaline phosphatase, bilirubin, and INR (clotting)
• Tests for other causes: viral hepatitis A, B, C and E, autoimmune hepatitis, alcohol, and gallstones
• Acetaminophen blood level when overdose is possible, interpreted with the time of ingestion
• Ultrasound of the liver and bile ducts
• Liver biopsy occasionally

Causality tools (such as the RUCAM score) and the NIH LiverTox database help judge how likely a drug is to be the cause.

Treatment

• Stop the suspected drug or supplement, unless your doctor advises otherwise. Most injuries improve within weeks to months.
• N-acetylcysteine (NAC) for acetaminophen overdose. It is highly effective when started early and is also used in some non-acetaminophen acute liver failure.
• Supportive care: fluids, nutrition and treatment of itching.
• Steroids for drug-induced autoimmune-like hepatitis or some immune checkpoint inhibitor injuries.
• Liver transplant for acute liver failure that does not recover.

Do not restart a drug that caused DILI. A second exposure can cause a faster and more severe reaction.

Outlook

Most people recover fully once the drug is stopped. A minority develop chronic liver injury. People with jaundice from hepatocellular injury have a higher risk of severe outcomes, which is why prompt assessment matters. Acetaminophen overdose treated early has an excellent outlook.

Prevention

• never exceed the label dose of acetaminophen, and check combination cold and flu products for hidden acetaminophen
• tell your doctor about all supplements and herbal products
• avoid heavy alcohol use with medicines processed by the liver
• attend recommended liver blood test monitoring for medicines such as methotrexate, TB drugs and some anti-seizure drugs

Frequently asked questions

Which medicines most often cause liver damage?

Acetaminophen overdose is the most common cause of acute liver failure in the US. At normal doses, antibiotics (especially amoxicillin-clavulanate), TB drugs, anti-seizure drugs, methotrexate and some herbal and bodybuilding supplements are frequent causes.

What are the symptoms of drug-induced liver injury?

Many people have no symptoms. Others notice tiredness, nausea, loss of appetite, right upper belly discomfort, dark urine, pale stools, itching and yellowing of the skin and eyes. Rash and fever can occur with allergic-type reactions.

Can the liver recover from drug damage?

Usually, yes. The liver regenerates well, and most people recover within weeks to months after stopping the drug. Severe cases can lead to liver failure needing transplant, and a small number develop long-term liver damage.

Can supplements damage the liver?

Yes. Green tea extract, anabolic steroids, some weight-loss and bodybuilding products, kava and others have caused serious liver injury. Supplements are less tightly regulated than medicines. Tell your doctor about any supplements you take.