Liver Injury, Drug- or Toxin-Induced

Key Features

Essentials of Diagnosis

• Can mimic viral hepatitis, biliary tract obstruction, or other types of liver disease

• In any patient with liver disease, clinicians must inquire about the use of many therapeutic agents, including over-the-counter herbal or dietary supplements

General Considerations

• Drug toxicity may be categorized on the basis of pathogenesis or histologic appearance

DIRECT HEPATOTOXICITY

• Dose-related severity

• A latent period following exposure

• Susceptibility in all individuals

• Examples include

  • Acetaminophen (toxicity enhanced by fasting and chronic alcohol use)

  • Alcohol

  • Amatoxins in mushroom poisoning

  • Carbon tetrachloride

  • Chloroform

  • Heavy metals

  • Mercaptopurine

  • Niacin

  • Plant alkaloids

  • Phosphorus

  • Pyrazinamide

  • Tetracyclines

  • Tipranavir

  • Valproic acid

  • Vitamin A

INDIRECT HEPATOTOXICITY

• Refers to liver injury that results when use of a drug leads to exacerbation of preexisting liver disease

• An example is a flare of HBV infection in the setting of immunosuppressive therapy for a nonhepatic autoimmune disease

IDIOSYNCRATIC REACTIONS

• Reactions are sporadic, not dose-related, and occasionally are associated with fever and eosinophilia (including drug rash with eosinophilia and systemic symptoms [DRESS] syndrome)

• May have genetic predisposition

• Usually reversible with discontinuation of the offending agent

• Risk factors for chronicity (> 1 year) are older age, dyslipidemia, and severe acute injury

• Examples include

  • Abacavir

  • Amiodarone

  • Aspirin

  • Carbamazepine

  • Chloramphenicol

  • Dapsone

  • Diclofenac

  • Disulfiram

  • Duloxetine

  • Ezetimibe

  • Flavocoxid (a "medical food")

  • Fluoroquinolones (moxifloxacin and levofloxacin, in particular)

  • Flutamide

  • Halothane

  • Isoniazid

  • Ketoconazole

  • Lamotrigine

  • Methyldopa

  • Natalizumab

  • Nevirapine

  • Oxacillin

  • Phenytoin

  • Pyrazinamide

  • Quinidine

  • Rivaroxaban

  • Streptomycin

  • Temolozomide

  • Thiazolidinediones

  • Tolvaptan

  • Tacrine (perhaps)

• Cholesterol-lowering agents, including statins

  • May cause serum aminotransferase elevations

  • Rarely cause true hepatitis and even more rarely cause acute liver failure

  • No longer considered contraindicated in patients with liver disease

CHOLESTASIS

• Noninflammatory (cholestasis alone):

  • Anabolic steroids containing an alkyl or ethinyl group at carbon 17

  • Azathioprine

  • Cetirizine

  • Cyclosporine

  • Diclofenac

  • Estrogens

  • Febuxostat

  • Indinavir (increased risk of indirect hyperbilirubinemia in patients with Gilbert syndrome)

  • Mercaptopurine

  • Methyltestosterone

  • Tamoxifen

  • Temozolomide

  • Ticlopidine

• Inflammatory (inflammation of portal areas with bile duct injury [cholangitis], often with allergic features such as eosinophilia):

  • Amoxicillin-clavulanic acid

  • Azathioprine

  • Azithromycin

  • Captopril

  • Celecoxib

  • Cephalosporins

  • Chlorothiazide

  • Chlorpromazine

  • Chlorpropamide

  • Erythromycin

  • Penicillamine

  • Prochlorperazine

  • Semisynthetic penicillins (eg, cloxacillin)

  • Sulfadiazine

ACUTE OR CHRONIC HEPATITIS

• Agents causing reactions that are clinically and histologically similar to autoimmune hepatitis

  • Aspirin

  • Isoniazid (increased risk in hepatitis B virus carriers)

  • Methyldopa

  • Minocycline

  • Nitrofurantoin

  • Nonsteroidal anti-inflammatory drugs

  • Propylthiouracil

  • Terbinafine

  • Tumor necrosis factor inhibitors

• Agents causing acute or chronic hepatitis

  • Cocaine

  • Diclofenac

  • Dimethyl fumarate

  • Efavirenz

  • Imatinib mesylate

  • Ipilimumab

  • Methylenedioxymethamphetamine (MDMA; Ecstasy)

  • Nafazodone (has an FDA "black box" warning)

  • Nevirapine

  • Pioglitazone

  • Ritonavir

  • Rosiglitazone

  • Saquinavir

  • Sulfonamides

  • Telithromycin

  • Zafirlukast

  • Various herbal and alternative remedies (eg, black cohosh, chaparral, garcinia cambogia, germander, green tea extracts, Herbalife™ products, Hydroxycut™ products, jin bu ...