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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 (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:

    • AIDS/HIV agents: Abacavir, nevirapine,

    • Antiarrhythmic agents: Quinidine, amiodarone

    • Antihypertensive agents: Methyldopa,

    • Antimicrobial agents: [0]Chloramphenicol, dapsone, fluoroquinolones (moxifloxcin, levofloxacin, in particular), ketoconazole, isoniazid, oxacillin, pyrazinamide, streptomycin

    • Antiseizure medications: Carbamazepine, lamotrigine, phenytoin,

    • Analgesic agents: Aspirin, diclofenac, duloxetine

    • Anticoagulant agent: Rivaroxaban

    • Chemo-immunotherapeutic agents: Flutamide, natalizumab, temozolomide,

    • Metabolic agents: Disulfiram, ezetimibe, thiazolidinediones, tolvaptan

  • 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):

    • Hormonal agents: Anabolic steroids containing an alkyl or ethinyl group at carbon 17, estrogens, methyltestosterone, tamoxifen

    • Immunosuppressants: Azathioprine, cyclosporine

    • Cetirizine

    • Diclofenac

    • Febuxostat

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

    • Mercaptopurine

    • Temozolomide

    • Ticlopidine

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

    • Antibiotics: Amoxicillin-clavulanic acid, azithromycin, cephalosporins, erythromycin, penicillamine, semisynthetic penicillins (eg, cloxacillin), Sulfadiazine

    • Antipsychotics: chlorpromazine, prochlorperazine

    • Azathioprine

    • Captopril

    • Celecoxib

    • Chlorothiazide

    • Pazopanib

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

    • HIV/AIDS agents: Efavirenz, nevirapine, ritonavir, saquinavir

    • Imatinib mesylate

    • Ipilimumab

    • Methylenedioxymethamphetamine (MDMA; Ecstasy)

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

    • Sulfonamides

    • Telithromycin

    • Thiazolidinediones: Pioglitazone, rosiglitazone

    • Zafirlukast

OTHER REACTIONS

  • Agents causing fatty liver, macrovesicular; examples include:

    • Alcohol

    • Amiodarone

    • Corticosteroids

    • Irinotecan

    • Methotrexate

    • Tamoxifen

    • Vinyl chloride (in exposed workers)

    • Zalcitabine

  • Agents causing fatty liver, microvesicular; examples include:

    • Didanosine

    • Stavudine

    • Tetracyclines

    • Valproic acid

    • Zidovudine

  • Agents causing granulomas

    • Allopurinol

    • Hydralazine

    • Pembrolizumab and other immune ...

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