Drug-induced cholestasis results from inhibition or genetic deficiency of various hepatobiliary transporter systems. The following drugs cause cholestasis: 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, and ticlopidine.
The following drugs cause inflammation of portal areas with bile duct injury (cholangitis [and, in some cases, bile duct loss]), often with allergic features such as eosinophilia: amoxicillin-clavulanic acid (among the most common causes of drug-induced liver injury), azathioprine, azithromycin, captopril, celecoxib, cephalosporins, chlorothiazide, chlorpromazine, chlorpropamide, erythromycin, mercaptopurine, penicillamine, prochlorperazine, semisynthetic penicillins (eg, cloxacillin), sulfadiazine, and temozolomide. Ketamine abuse may cause secondary biliary cirrhosis. Cholestatic and mixed cholestatic-hepatocellular toxicity is more likely than pure hepatocellular toxicity to lead to chronic liver disease.
B. Acute or Chronic Hepatitis
Medications that may result in acute or chronic hepatitis that is histologically and, in some cases, clinically similar to autoimmune hepatitis include minocycline and nitrofurantoin, most commonly, as well as aspirin, isoniazid (increased risk in HBV and HCV carriers), methyldopa, nonsteroidal anti-inflammatory drugs, propylthiouracil, terbinafine, tumor necrosis factor inhibitors, and varenicline. Histologic features that favor a drug cause include portal tract neutrophils and hepatocellular cholestasis. Hepatitis also can occur in patients taking cocaine, diclofenac, dimethyl fumarate, efavirenz, imatinib mesylate, ipilimumab, nivolumab, and other checkpoint inhibitors, methylenedioxymethamphetamine (MDMA; Ecstasy), nefazodone (has a black box warning for a potential to cause liver failure), nevirapine (like other protease inhibitors, increased risk in HBV and HCV carriers), pioglitazone, ritonavir (greater rate than other protease inhibitors), rosiglitazone, saquinavir, sulfonamides, telithromycin, and zafirlukast, as well as a variety of alternative remedies (eg, black cohosh, chaparral, garcinia cambogia, germander, green tea extract, Herbalife products, Hydroxycut, jin bu huan, kava, saw palmetto, skullcap, usnic acid, and other traditional Chinese herbal preparations), in addition to dietary supplements (eg, 1, 3-dimethylamylamine in OxyELITE Pro, a weight-loss supplement withdrawn from the US market).
This type of liver injury may be produced by alcohol, amiodarone, corticosteroids, haloperidol, irinotecan, lomitapide, methotrexate, mipomersen, tamoxifen, vinyl chloride (in exposed workers), zalcitabine, and possibly oxaliplatin.
Often resulting from mitochondrial injury, this condition is associated with aspirin (Reye syndrome), didanosine, linezolid, stavudine, tetracyclines, valproic acid, and zidovudine.
Allopurinol, hydralazine, pembrolizumab and other immune checkpoint inhibitors, phenytoin, pyrazinamide, quinidine, quinine, sulfasalazine, and vemurafenib can lead to granulomas and, in some cases, granulomatous hepatitis.
3. Fibrosis and cirrhosis
Methotrexate and vitamin A are associated with fibrosis and cirrhosis.
4. Sinusoidal obstruction syndrome (veno-occlusive disease)
This disorder may result from treatment with antineoplastic agents (eg, pre–bone marrow transplant, busulfan, gemtuzumab ozogamicin, inotuzumab ozogamicin, oxaliplatin) and pyrrolizidine alkaloids (eg, comfrey).
5. Peliosis hepatis (blood-filled cavities)
Peliosis hepatis may be caused by anabolic steroids and oral contraceptive steroids as well as azathioprine and mercaptopurine, which may also cause nodular regenerative hyperplasia and other forms of liver injury.
6. Nodular regenerative hyperplasia
Nodular regenerative hyperplasia may be caused by azathioprine, oxaliplatin, and thioguanine.
Neoplasms may result from therapy with oral contraceptive steroids, including estrogens (hepatic adenoma but not focal nodular hyperplasia) and vinyl chloride (angiosarcoma).