Diagnosis

Drug-induced liver injury

Etiology

Classification of drug hepatoxicity

• Intrinsic (predictable and reproducible): acetaminophen [onh]

• Idiosyncratic (unpredictable) [veh][bis]

  • Antibiotics: amoxicillin-clavulanate, trimethoprim-sulfa, ciprofloxacin, isoniazid

  • NSAIDs

  • Herbal and dietary supplements: green tea extract, anabolic steroids

  • Cardiovascular drugs: statins, amiodarone

  • Central nervous system (CNS) agents: valproate, phenytoin

  • Antineoplastic: tyrosine kinase inhibitors, TNF-inhibitors, α-inhibitors, methotrexate

Cause [dbz][goc]

1. Acute cytotoxic or cytolytic damage: Hepatocellular pattern

   • Necrosis with panacinar ballooning: Amino salicylic acid, halothane, indomethacin, isoniazid, methyldopa, nitrofurantoin, sulfonamides, green tea leaf, chaparral (creosote bush, Larrea tridentata)

   • Mononucleosis-like hepatitis: Dapsone, phenytoin, amino salicylic acid, sulfonamides

   • Submassive percentral necrosis: Acetaminophen, poisoning by death cap mushrooms (Amanita phalloides), copper, halothane, ketoconazole, propylthiouracil, trichlorethylene, carbon tetrachloride, germander (Teucrium genus), Pennyroyal (pennyroyal, Hedeoma pulegioides), ferrous sulfate and phosphorus poisoning

   • Massive necrosis: Phenytoin, halothane, isoniazid, Kava (Piper methysticum)

2. Acute steatosis resembling NASH:

   • Microvesicular steatosis: Acetylsalicylic acid, alcohol, aflatoxin, amiodarone,

     valproic acid, calcium, cocaine, piroxicam, tetracycline (IV administration)

   • Macrovesicular steatosis: Alcohol, asparaginase, NSAIDs, corticosteroids,

     didanosine, phosphorus poisoning, linezolid, methotrexate, metoprolol, mercury, minocycline parenteral nutrition, nifedipine, chemotherapeutic agents, tetracycline

   • Steatohepatitis: Alcohol, amiodarone, chemotherapeutic agents, didanosine, synthetic estrogens, nifedipine, methotrexate, tamoxifen

3. Cholestatic pattern: sepsis, heart failure, and viral hepatitis must be ruled out

4. Mixed pattern of cholestatic and hepatocellular damage:

   • Acute cholestasis with ductal injury or cholangitis: Allopurinol, carbamazepine, hydralazine, paraquat

   • Pure or soft cholestasis: Oral contraceptives, azathioprine, anabolic steroids, estrogen, methimazole, mercaptopurne

   • Hepatocellular and cholestatic: Captopril, Coumadin, erythromycin, ethambutol, phenothiazines, phenylbutazone, griseofulvin, isoniazid, methimazole, total parenteral nutrition, thiazides, verapamil

5. Chronic drug induced liver disease: toxic agent > 6 months

   • Autoimmune-like hepatitis: Lisinopril, methotrexate, sulphonamides, tamoxifen, trazodone, uracil, alpha-metyldopa, clometasin, NSAIDs, statins, anti-TNF-α, infliximab, hydralazine, nitrofurantoin, minocycline, minocycline, oxyphenisatin acetate, adalimumab, etanercept, efalizumab, ipilimumab, atomoxetine, dihydralazine, fenofibrate, pemoline, warfarin

   • Primary biliary cirrhosis like damage: Ajmaline, oral contraceptives, amitriptyline, ampicillin, barbiturates, benoxaprofen, carbamazepine, cimetidine, chlorpromazine, phenytoin, haloperidol, ketoconazole, methyltestosterone, thiabendazole, tolbutamide

   • Primary sclerosing cholangitis-like damage: Floxuridine (intra-arterial infusion), formalin for steriization of echinococcal cysts

   • Ductopenia: Aceprometazine, ajmaline, amitriptyline, amoxicilin, ampicillin, azathioprine, azithromycin, barbiturates, chlorothiazide, clindamycin, diazepam, erythromycin, ibuprofen, phenytoin, tetracycline, thiabendazole, trimethoprim

6. Vascular damage:

   • Sinusoidal dilation: Oral contraceptives

   • Peliosis hepatis (large spaces filled with red blood cells without endothelial lining): Anabolic steroids, azathioprine, oral contraceptives, danazol, hypervitaminosis A and tamoxifen

   • Phlebosclerosis: alcohol and heroin

   • Ischemic hepatitis: amiodarone (i.v.)

   • Veno-occlusive: Teas containing the pyrrolizidine alkaloids, alcohol, excessive vitamin A, azathioprine, dacarbazine, cyclophosphamide, oxipltinum, complication of chemotherapy and radiation therapy following bone marrow transplantation

   • Budd-Chiari syndrome: oral contraceptives

   • Damage to hepatic arteries and arterioles results from hypersensitivity (angiitis leading to thickening of the arterial walls): Sulfonylureas, penicillin, phenytoin and allopurinol

   • Hepatoportal sclerosis: Arsenic, azathioprine, antiretrovirals such as didanosine

7. Granulomatous reactions: Antibiotics (amoxicillin, cephalexin, dicloxacillin, interferon, isoniazid, nitrofurantoin, quinine, penicillin, sulfonamides), anticonvulsants (carbamazepine, chlorpromazine, diazepam, phenytoin), allopurinol, amiodarone, aspirin, anti TB vaccine, dapsone, methyldopa, mineral oil, talc

8. Liver fibrosis and cirrhosis: alcohol, hypervitaminosis A, chemotherapy, methotrexate, amiodarone, isoniazid, iproniazid, valproic acid

9. Neoplasia and pseudotumors: thorotrast, arsenic, vinyl chloride, oral contraceptives, anabolic steroids, danazol, carbamazepine, azathioprine

Pathophysiology

1. Drugs or their metabolites:

   • Cause direct cell stress

   • Trigger immune reactions

   • Impair mitochondrial function

2. May lead to mitochondrial permeability transition

3. This can initiate apoptotic or necrotic cell death, depending on the availability of ATP

Complications [bis]

• Acute liver failure

• Chronic liver disease

Epidemiology

Incidence per 100.000 [v5s][bsz][wpe][fsc][ana][goc][yv4][dbz]

Approach

• Liver damage induced by drugs, toxins, herbal products or homeopathic treatments can mimic any pattern of primary liver disease [dbz]

• The manifestations of drug hepatotoxicity are highly variable, ranging from asymptomatic elevation of liver enzymes to fulminant hepatic failure [ya2]

• Diagnostic scales (CIOMS/RUCAM) can support the causality assessment

• Blood test: ASAT, ALAT, GGT, ALP, Bilirubin, PT-INR

• Hepatitis viral serology

• Antinuclear antibodies

• Copper and iron levels

• Abdominal ultrasound

• CT/MRI scan

• Liver biopsy: the gold standard for the diagnosis of drug-induced hepatotoxicity [dbz]

Treatment

1. Discontinuation of the suspected drug [bis]

2. Supportive care

3. N-acetylcysteine for acetaminophen hepatotoxicity

4. Corticosteroids used in oncology to manage hepatotoxicity [ya2]

5. Ursodeoxycholic acid traditionally used to treat cholestasis [ya2]

6. Liver transplantation: Kings college criteria

   • Paracetamol-induced hepatotoxicity:

     • pH < 7.3 or

     • arterial lactate >3.5 at 4 hours or >3.0 at 12 hours or

     • PT > 100 sec (PT-INR > 6.5)

     • Creatinine >300 mol/l (3.4 mg/dl)

     • Grade 3 or 4 encephalopathy

   • Non-paracetamol-induced hepatotoxicity:

     • Prothrombin time > 100 s (PT-INR > 6.5) or

     • Any three of the following:

       1. Age < 11 years or age > 40 years

       2. Etiology of non-A/non-B hepatitis, halothane hepatitis, or idiosyncratic drug reactions

       3. Duration of jaundice of more than 7 days before onset of encephalopathy

       4. Prothrombin time greater than 50s (INR > 3.5)

       5. Serum bilirubin level greater than 300 umol/l (17 mg/dl)

Differential diagnoses

Acute liver failure, Alcoholic liver disease, Autoimmune hepatitis, Cholangiocarcinoma, Cholangitis, Choledocholithiasis, Cytomegalovirus, Gilbert syndrome, Heart failure, Hemochromatosis, Hepatocellular carcinoma, Lymphoma, Mononucleosis, Nonalcoholic fatty liver disease, Pancreatic cancer, Primary biliary cirrhosis, Primary sclerosing cholangitis, Viral hepatitis, Wilson's disease