Hepatotoxicity, Liver Diseases Side Effect

Hepatotoxicity is a liver dysfunction or liver damage due to drugs, toxins, dietary supplements, phytotherapeutics , and other substances. Untreated drug-induced liver injury can progress to liver failure.

Drug-induced liver disease is usually indistinguishable from liver injury of other causes. In most cases hepatic symptoms caused by a medication subside after cessation of the causative agent.

Most symptoms of drug-induced liver damage are similar to the symptoms of acute hepatitis and cholestasis. Drug-induced liver injury is characterized by significant elevations in the serum alanine aminotransferase (ALT), which usually precede elevations in total bilirubin levels and alkaline phosphatase levels. Most injuries occur within 1 year of initiating the offending agent.

Antibiotics are the most common cause of liver injury, followed by neuropsychiatric drugs, immunomodulatory agents, antihypertensives, analgesics, and lipid-lowering medications37.

Drug Incidence
Acetaminophen (paracetamol, Tylenol®)36 Metabolites of acetaminophen are generated by CYP450s and damage hepatocytes. The induction of these enzymes may enhance acetaminophen toxicity. Blood levels are directly related to the risk of hepatotoxicity. High doses >10–15 g lead to liver injury ranging from elevated aminotransferases to acute liver failure.
Alka-Seltzer Plus
Alkeran Rare
Allopurinol reports of granulomatous hepatitis 23
Amiodarone (Cordarone®)33 abnormal liver biochemical tests in 15% to 80% of patients, seriouse liver disease, rare cases of acute liver failure
amiodarone-induced liver disease may proceed despite discontinuation of amiodarone 34
Amoxicillin-Clavulanate hepatotoxicity is mainly related to the clavulanic acid component, incidence is 1.7
cases per 10 000 patients, risk factors are male gender, age over 55 years, prolonged use 29
Amodiaquine (Camoquin®, Flavoquine®)5
Anabolic Steroids produce reversible cholestasis 26
Asacol Rare
Acarbose (Precose®, Prandase®) rare
Aspirin hepatotoxicity occurs when blood salicylate concentrations exceed 25 mg/100 mL
Bosentan (Tracleer®)39
Carbamazepine (Tegretol®) may cause granulomatous hepatitis 22
Captopril (Capoten®)12
CellCept 3% to 20%
Chlorpromazine (Thorazine®) cholestatic hepatitis28, asymptomatic liver biochemical test abnormalities in 20% to 50% of patients, and rare cases of fulminant hepatic necrosis
Cyclosporine (Neoral®) 1% to 7%, inhibits transport of bile acid and commonly causes mild increases in serum bilirubin concentrations
Dantrolene (Dantrium®) 1%
case-fatality rate of about 28% 20
Dextropropoxyphene32 reports of cholestasis with bile duct injury
Diclofenac (Voltaren®, Cataflam®) elevated serum aminotransferase levels occur in up to 15% of patients, reports of chronic hepatitis 24, the risk of diclofenac-induced hepatitis is increased in women and with aging
Diltiazem (Cardizem®, Dilacor XR ®, Tiazac®)
Disulfiram (Antabuse)10
Duloxetine (Cymbalta®)41
Enalapril (Vasotec®)12
Fluconazole (Diflucan®) causes mild transient elevation of transaminase levels, fluconazole is less hepatotoxic than ketoconazole and terbinafine15
Gemzar Rare
Gengraf 1% to 7%
Gleevec 6% to 12%
Ibuprofen (Motrin®)18
Intron A Rare
Isoniazid (Laniazid®, Nydrazid®, Rimifon®, Tubizid®)13 hepatitis develops in 21 per 1000 paients, about 5-10% of cases are fatal
Isotretinoin (Accutane®)
Itraconazole (Sporanox®) Rare
Ketoconazole (Nizoral®)14 5% to 17%
symptomatic hepatitis occurs in 7-20 of 100 000 exposed patients, onset of toxicity within 6 to 12 weeks
Lamotrigine (Lamictal®)35 1%, hepatotoxicity of lamotrigine represents immuno-allergic reaction called anticonvulsant hypersensitivity syndrome
Lansoprazole (Prevacid®)
Levofloxacin (Levaquin®) rare 30, 31
Leukine 13%
Mebaral < 1%
Methyldopa (Aldomet®)8 may cause immunoallergic drug hepatitis
Minocycline causes several types of liver damage, acute hepatitis, chronic hepatitis with autoimmune features 25
Mirtazapine (Remeron®)18
Moxifloxacin (Avelox®) rare 30, 31
Niacin (Nicotinic Acid)
Nitrofurantoin (Furadantin®, Macrodantin®, Macrobid®)6 risk of liver toxicity increases with age particularly after 64, nitrofurantoin has been associated with acute hepatitis, occasionally with features of cholestasis, hepatic granulomas, acute liver failure, and cirrhosis 7
Norvir < 2%
Oral Contraceptive Steroids 27 cholestasis develops in 2.5 per 10 000 women exposed
Omeprazole (Prilosec®)36
Pentobarbital (Nembutal®)
Phenytoin (Dilantin®, Phenytek®)9 causes serious idiosyncratic reaction that occurs in less than 1 per 10 000 persons
Pioglitazone (Actos®) does not share the hepatotoxic profile of troglitazone 16
Purinethol® Frequent
Reyataz® < 3%
Riluzole (Rilutek®)21
Risperdal Rare
Roferon-A Rare
Sandimmune 1% to 7%
Tacrolimus (Prograf®) 3% to 15%
Terbinafine (Lamisil®)3 rare cases of liver failure have been reported
Thiabendazole (Mintezol®)
Tikosyn > 2%
Trasylol 0.5%
Trimethoprim-Sulfamethoxazole hepatotoxicity mostly attributed to the sulfonamide component, sulfa-hepatotoxicity is associated with a systemic hypersensitivity
trimethoprim has been associated with some cases of cholestatic hepatitis that occurs in 1.4 cases per 100,000 exposed patients
Valproic Acid (Sodium Valproate, Depakene®, Depakote®)4 occurs generally in children younger than 3 years of age
Venlafaxine (Effexor®)17
Verapamil (Covera-HS®)11
Xeloda < 5%


Discontinuation of the offending medication generally results in normalization of liver enzyme levels and functon.

Risk factors for developing hepatotoxicity:

  • Drug dose
  • Half-life of the drug. Long-acting medications are more likely to cause injury than short-acting medications.
  • Female sex
  • Old age. Elderly are at increased risk of liver disease, while liver toxicity is rare in children.
  • Use of concomitant medications.
  • Genetic polymorphism, familial cases
  • Chronic alcohol use
  • Underlying diseases, e.g. preexisting liver disease, obesity, diabetes, renal failure, active or chronic hepatitis
  • Nutritional deficiency


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Published: August 16, 2016
Last updated: December 14, 2017

  • Drug-induced liver injury is one of the most common reasons for withdrawal of an approved medicine.

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