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For further information, see CMDT Part 16-09: Drug- or Toxin-Induced Liver Injury

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

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, chaparral, germander, green tea extracts, Herbalife™ products, Hydroxycut™ products, jin bu huan, kava, saw palmetto, skullcap, possibly black cohosh and some traditional Chinese herbal preparations)

OTHER REACTIONS

  • Agents causing fatty liver, macrovesicular

    • Alcohol

    • Amiodarone

    • Corticosteroids

    • Irinotecan

    • Lomitapide

    • Oxaliplatin (possibly)

    • Methotrexate

    • Mipomersen

    • Tamoxifen

    • Vinyl chloride (in exposed workers)

    • Zalcitabine

  • Agents causing fatty liver, microvesicular

    • Didanosine

    • Stavudine

    • Tetracyclines

    • Valproic acid

    • Zidovudine

  • Agents causing granulomas...

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