Liver Toxicity (Hepatotoxicity)

How substances damage the liver

The liver processes most drugs and chemicals, converting them into forms the body can eliminate. This makes it vulnerable:

• Dose-dependent (intrinsic) toxicity: predictable damage once a threshold is exceeded. Acetaminophen is the classic example: in overdose, a toxic by-product (NAPQI) overwhelms the liver's defenses.
• Idiosyncratic toxicity: unpredictable reactions in a small number of people at normal doses, related to genetics, the immune system or how the person metabolizes the drug. They usually appear within days to months of starting a medicine.

Patterns of injury

Common causes

Medicines

• acetaminophen (paracetamol): overdose, or regular doses above the label maximum, especially with alcohol or fasting. See poisoning due to analgesics
• antibiotics: amoxicillin-clavulanate (the most common cause of idiosyncratic DILI in many countries), nitrofurantoin, minocycline, sulfonamides
• tuberculosis drugs: isoniazid, rifampin, pyrazinamide
• anti-seizure medicines: valproate, carbamazepine, phenytoin
• methotrexate, amiodarone, some statins (rarely serious), ketoconazole and some other antifungals
• immune checkpoint inhibitors for cancer
• NSAIDs such as diclofenac

Herbal and dietary supplements

• green tea extract (concentrated, not brewed tea)
• turmeric and curcumin supplements (rare cases)
• kava, comfrey, chaparral, germander and kratom
• ashwagandha (case reports)
• anabolic steroids and bodybuilding supplements
• high-dose vitamin A and niacin
• multi-ingredient weight-loss products

Supplements are not reviewed for safety before sale in the US, and products can be contaminated or contain undeclared ingredients.

Alcohol

Heavy drinking causes fatty liver, alcoholic hepatitis and cirrhosis, and increases susceptibility to drug-related liver injury. See alcoholic hepatitis.

Chemicals and toxins

• solvents such as carbon tetrachloride and vinyl chloride
• poisonous mushrooms (Amanita phalloides, "death cap")
• aflatoxin from moldy grains and nuts

Symptoms

Many people have no symptoms and are found on blood tests. When present:

• fatigue and loss of appetite
• nausea and vomiting
• right upper belly discomfort
• jaundice (yellow skin and eyes), dark urine and pale stools
• itching
• fever, rash and swollen glands in allergic-type reactions

Signs of liver failure include confusion (hepatic encephalopathy), easy bruising and bleeding, fluid in the belly and low blood sugar.

Diagnosis

DILI is a diagnosis of exclusion. Doctors will:

• take a careful history of all medicines, supplements, herbal products, alcohol and exposures over the previous 6 months, including timing
• order liver tests (ALT, AST, alkaline phosphatase, bilirubin, INR and albumin)
• test for viral hepatitis (A, B, C and E), autoimmune hepatitis and other liver diseases
• perform an ultrasound to check for gallstones, bile duct blockage and liver structure
• check acetaminophen levels when relevant
• consult the NIH LiverTox database for the known liver risk of each substance
• sometimes do a liver biopsy

Clinical scoring tools such as RUCAM help estimate how likely a drug is responsible.

Treatment

• Stop the suspected drug or supplement. In most idiosyncratic cases, liver tests improve within weeks to months.
• Acetaminophen overdose: acetylcysteine (NAC) as soon as possible, ideally within 8 hours.
• Mushroom poisoning: hospital treatment, sometimes with specific antidotes.
• Supportive care: rest, nutrition, fluids, and treatment of itching.
• Corticosteroids for drug-induced autoimmune-like hepatitis or immune checkpoint inhibitor hepatitis.
• Liver transplant for acute liver failure that does not recover.

Do not restart the drug that caused the injury. Re-exposure can cause a faster, more severe reaction.

Prevention

• follow label doses, and check all products for acetaminophen to avoid doubling up
• tell your doctor and pharmacist about all supplements and herbal products
• limit alcohol, especially while taking medicines that affect the liver
• attend liver test monitoring if your medicine requires it
• be cautious with weight-loss, bodybuilding and multi-ingredient supplements
• never eat wild mushrooms unless identified by an expert

Frequently asked questions

What is liver toxicity?

Liver toxicity is damage to the liver caused by chemicals, including prescription and over-the-counter medicines, herbal and dietary supplements, alcohol and industrial toxins. It ranges from mild abnormal blood tests to life-threatening liver failure.

What are the signs of liver damage from medication?

Signs include fatigue, nausea, loss of appetite, right upper belly discomfort, itching, dark urine, pale stools and yellowing of the skin or eyes. Many cases have no symptoms and are detected only by blood tests.

Which supplements can damage the liver?

Concentrated green tea extract, anabolic steroids and bodybuilding products, kava, comfrey, kratom, high-dose vitamin A and niacin, and some multi-ingredient weight-loss products have been linked to liver injury. Turmeric and ashwagandha have rare case reports.

Can the liver heal from drug damage?

Usually, yes. The liver has a strong capacity to regenerate. Once the cause is stopped, most people recover within weeks to months. Severe cases can progress to liver failure, and a small number develop chronic liver injury.

How much acetaminophen damages the liver?

Taking more than the label maximum can cause liver injury, and some people are at risk at lower amounts, including those who drink heavily, are fasting or malnourished, or have liver disease. Follow label limits and check combination products to avoid doubling up.