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 (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

  • Alzheimer disease agent: atabecestat

  • Antiarrhythmic agents: Quinidine, amiodarone

  • Antihypertensive agent: Methyldopa

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

  • Antiseizure medications: Carbamazepine, lamotrigine, phenytoin

  • Analgesic agents: Aspirin, diclofenac, duloxetine

  • Anticoagulant agent: Rivaroxaban

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

  • Gene therapy: abeparvovec

  • Metabolic agents: Disulfiram, ezetimibe, thiazolidinediones, tolvaptan

  • Monoclonal antibody therapy: alemtuzumab

• 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

CHOLESTATIC INJURY

• 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

HEPATOCELLULAR INJURY

• 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 ...