The document discusses various causes of drug-induced liver injury including direct toxicity from drugs like acetaminophen and carbon tetrachloride as well as idiosyncratic reactions. Certain drugs are more likely to cause hepatotoxicity through both direct toxicity and idiosyncratic mechanisms. Supportive treatment measures for acetaminophen overdose-induced liver injury are also outlined. Herbal and dietary supplements can also potentially cause liver injury through mechanisms like pyrrolizidine alkaloid contamination.

2. Inhalation, Ingestion, parenteral administration Industrial toxins (CCl4, yellow phosphorus) Mushroom poisoning (Amenita, Galerina) Pharmacologic agents

3. Direct toxic Carbon tetrachloride Acetaminophen Halothane Idiosyncratic

4. Hepatitis occurs with predictable regularity Dose-dependent Latent period short (several hours) Clinical manifestations may be delayed (24- 48 hours) CCl4, phosphorus, Amanita mushroom, Tetracycline Liver injury may go unrecognized until the onset of jaundice

5. Hepatitis is infrequent (1 in 1000-10000 px) Unpredictable Response is not dose-dependent Liver injury may occur during or shortly after exposure to the drug Isoniazid, phenytoin, statins, oral contraceptives Extrahepatic manifestations: rash, fever, arthralgia, leukocytosis, eosinophilia

6. Cholestasis Fatty liver Hepatitis Mixed hepatitis/cholestasis Toxic (necrosis) Grnulomas

7. Methyl testosterone Erythromycin Rifampin Amoxicillin-clavulanic Oxacillin Clopidogrel Irbersartan Nifedipine Verapamil Methimazole Sulindac Ezetimibe Tamoxifen Mestranol Chlorpropamide Chlorpromazine

8. Amiodarone Tertracycline (high dose IV) Valproic acid Antiviral protease inhibitors (indinavir, ritonavir) Methorexate

9. Halothane Isoniazid (INH) Rifampin Pyrazinamide (PZA) Phenytoin Carbamazine Ketoconazole Fluconazole Itraconazole Methyldopa Captopril Losartan Ibuprofen Diclofenac Indomethacin Sulindac Nifedipine Verapamil Diltiazem Chlorothiazide Troglitazone Acarbose Antiviral Protease inhibitors (ritnavir, idinavir)

10. Amoxicillin/Clavulanic acid Trimethoprim/Sulfamethoxazole Azathioprine Nicotinic acid Lovastatin Ezetimibe

11. Acetaminophen Carbon tetrachloride Yellow phosphorus Amanita phalloides Dimethylformamide

12. Quinidine Sulfonamides Carbamazine Allopurinol

13. Direct toxin Common in US and UK Single dose of 10-15 grams  liver injury >25 grams  fatal Pain, nausea, vomiting, diarrhea in 4-12 hrs Liver failure in 24-48 hrs Aminotranferase levels app 10,000 units In alcoholics, toxic dose may be 2 grams

14. Supportive measures Gastric lavage Activated charcoal or cholestyramine (prevent absorption); should be given within 30 mins N-acetylcysteine given within 8 hrs; loading dose-140/kg, ff by 70mg/kg q 4 hrs x 15-20 doses Survivors have no evidence of hepatic sequelae

15. Idiosyncratic type 1% of cases: hepatitis-like syndrome Aminotransferases < 200 units; return to normal in few weeks whether INH is continued or not Liver morphology: hepatitis-like Toxicity increases wit age; > 50 yrs old Enhanced by alcohol, rifampin, pyrazinamide

16. Idiosyncratic type Steven Johnson’s syndrome: exfoliative dermatitis, fever, lymphadenopathy; leukocytosis, eosinopilia  immune mediated hypersensitivity mechanism Liver morphology: hepatitis-like picture (majority); cholestasis (rare)

17. Toxic and idiosyncratic reaction 15-50% have modest elevations of aminotransferases, which may remain stable or decrease despite continuation of the drug Liver morphology: fatty liver Direct hepatoxic effect Liver injury may persist for months after discontinuation ( long half-life)

18. More common in children Cholestatic type Idiosyncratic reaction Nausea, vomiting, fever, RUQ pain, jaundice, leukocytosis, elevated aminotransferases Clinical improvement upon drug withdrawal No evidence of CLD on follow up

19. Combination of estrogenic and progestational steroids; estrogen is primarily responsible Intrahepatic cholestasis Pruritus and jaundice Susceptible patients: idiopathic jaundice of pregnancy, family history Focal nodular hyperplasia, adenomas

20. Jin Bu Huan Xiao chai hu tang Senna Mistletoe Skull cap Ma huang Bee pollen Valerian root Kava Caelandine Impila Herbal tea

21. Pyrrolizidine alkaloids may contaminate Chinese herbal meds  venoocclusive disease  sinusoidal hepatic vein obstruction Active metabolites, which maybe potentiated by alcohol and drugs that stimulate cytochrome P450 Alternative meds may also stimulate cytochrome P450  amplify the hepatotoxicity of drug hepatotoxins