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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

    • Disulfuram

    • 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

    • Oxaliplatin (possibly)

    • Methotrexate

    • Tamoxifen

    • Vinyl chloride (in exposed workers)

    • Zalcitabine

  • Agents causing fatty liver, microvesicular

    • Didanosine

    • Stavudine

    • Tetracyclines

    • Valproic acid

    • Zidovudine

  • Agents causing granulomas

    • Allopurinol

    • Quinidine

    • Quinine

    • Phenytoin

    • Pyrazinamide

  • Agents causing fibrosis and cirrhosis

    • Methotrexate

    • Vitamin A

    • Ketamine abuse (secondary biliary ...

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