Toxic and drug induced hepatitis

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Toxic and drug induced hepatitis

  1. 2. <ul><li>Inhalation, Ingestion, parenteral administration </li></ul><ul><li>Industrial toxins (CCl4, yellow phosphorus) </li></ul><ul><li>Mushroom poisoning (Amenita, Galerina) </li></ul><ul><li>Pharmacologic agents </li></ul>
  2. 3. <ul><li>Direct toxic </li></ul><ul><li>Carbon tetrachloride </li></ul><ul><li>Acetaminophen </li></ul><ul><li>Halothane </li></ul><ul><li>Idiosyncratic </li></ul>
  3. 4. <ul><li>Hepatitis occurs with predictable regularity </li></ul><ul><li>Dose-dependent </li></ul><ul><li>Latent period short (several hours) </li></ul><ul><li>Clinical manifestations may be delayed (24- 48 hours) </li></ul><ul><li>CCl4, phosphorus, Amanita mushroom, Tetracycline </li></ul><ul><li>Liver injury may go unrecognized until the onset of jaundice </li></ul>
  4. 5. <ul><li>Hepatitis is infrequent (1 in 1000-10000 px) </li></ul><ul><li>Unpredictable </li></ul><ul><li>Response is not dose-dependent </li></ul><ul><li>Liver injury may occur during or shortly after exposure to the drug </li></ul><ul><li>Isoniazid, phenytoin, statins, oral contraceptives </li></ul><ul><li>Extrahepatic manifestations: rash, fever, arthralgia, leukocytosis, eosinophilia </li></ul>
  5. 6. <ul><li>Cholestasis </li></ul><ul><li>Fatty liver </li></ul><ul><li>Hepatitis </li></ul><ul><li>Mixed hepatitis/cholestasis </li></ul><ul><li>Toxic (necrosis) </li></ul><ul><li>Grnulomas </li></ul>
  6. 7. <ul><li>Methyl testosterone </li></ul><ul><li>Erythromycin </li></ul><ul><li>Rifampin </li></ul><ul><li>Amoxicillin-clavulanic </li></ul><ul><li>Oxacillin </li></ul><ul><li>Clopidogrel </li></ul><ul><li>Irbersartan </li></ul><ul><li>Nifedipine </li></ul><ul><li>Verapamil </li></ul><ul><li>Methimazole </li></ul><ul><li>Sulindac </li></ul><ul><li>Ezetimibe </li></ul><ul><li>Tamoxifen </li></ul><ul><li>Mestranol </li></ul><ul><li>Chlorpropamide </li></ul><ul><li>Chlorpromazine </li></ul>
  7. 8. <ul><li>Amiodarone </li></ul><ul><li>Tertracycline (high dose IV) </li></ul><ul><li>Valproic acid </li></ul><ul><li>Antiviral protease inhibitors (indinavir, ritonavir) </li></ul><ul><li>Methorexate </li></ul>
  8. 9. <ul><li>Halothane </li></ul><ul><li>Isoniazid (INH) </li></ul><ul><li>Rifampin </li></ul><ul><li>Pyrazinamide (PZA) </li></ul><ul><li>Phenytoin </li></ul><ul><li>Carbamazine </li></ul><ul><li>Ketoconazole </li></ul><ul><li>Fluconazole </li></ul><ul><li>Itraconazole </li></ul><ul><li>Methyldopa </li></ul><ul><li>Captopril </li></ul><ul><li>Losartan </li></ul><ul><li>Ibuprofen </li></ul><ul><li>Diclofenac </li></ul><ul><li>Indomethacin </li></ul><ul><li>Sulindac </li></ul><ul><li>Nifedipine </li></ul><ul><li>Verapamil </li></ul><ul><li>Diltiazem </li></ul><ul><li>Chlorothiazide </li></ul><ul><li>Troglitazone </li></ul><ul><li>Acarbose </li></ul><ul><li>Antiviral Protease inhibitors (ritnavir, idinavir) </li></ul>
  9. 10. <ul><li>Amoxicillin/Clavulanic acid </li></ul><ul><li>Trimethoprim/Sulfamethoxazole </li></ul><ul><li>Azathioprine </li></ul><ul><li>Nicotinic acid </li></ul><ul><li>Lovastatin </li></ul><ul><li>Ezetimibe </li></ul>
  10. 11. <ul><li>Acetaminophen </li></ul><ul><li>Carbon tetrachloride </li></ul><ul><li>Yellow phosphorus </li></ul><ul><li>Amanita phalloides </li></ul><ul><li>Dimethylformamide </li></ul>
  11. 12. <ul><li>Quinidine </li></ul><ul><li>Sulfonamides </li></ul><ul><li>Carbamazine </li></ul><ul><li>Allopurinol </li></ul>
  12. 13. <ul><li>Direct toxin </li></ul><ul><li>Common in US and UK </li></ul><ul><li>Single dose of 10-15 grams  liver injury </li></ul><ul><li>>25 grams  fatal </li></ul><ul><li>Pain, nausea, vomiting, diarrhea in 4-12 hrs </li></ul><ul><li>Liver failure in 24-48 hrs </li></ul><ul><li>Aminotranferase levels app 10,000 units </li></ul><ul><li>In alcoholics, toxic dose may be 2 grams </li></ul>
  13. 14. <ul><li>Supportive measures </li></ul><ul><li>Gastric lavage </li></ul><ul><li>Activated charcoal or cholestyramine (prevent absorption); should be given within 30 mins </li></ul><ul><li>N-acetylcysteine given within 8 hrs; loading dose-140/kg, ff by 70mg/kg q 4 hrs x 15-20 doses </li></ul><ul><li>Survivors have no evidence of hepatic sequelae </li></ul>
  14. 15. <ul><li>Idiosyncratic type </li></ul><ul><li>1% of cases: hepatitis-like syndrome </li></ul><ul><li>Aminotransferases < 200 units; return to normal in few weeks whether INH is continued or not </li></ul><ul><li>Liver morphology: hepatitis-like </li></ul><ul><li>Toxicity increases wit age; > 50 yrs old </li></ul><ul><li>Enhanced by alcohol, rifampin, pyrazinamide </li></ul>
  15. 16. <ul><li>Idiosyncratic type </li></ul><ul><li>Steven Johnson’s syndrome: exfoliative dermatitis, fever, lymphadenopathy; leukocytosis, eosinopilia  immune mediated hypersensitivity mechanism </li></ul><ul><li>Liver morphology: hepatitis-like picture (majority); cholestasis (rare) </li></ul>
  16. 17. <ul><li>Toxic and idiosyncratic reaction </li></ul><ul><li>15-50% have modest elevations of aminotransferases, which may remain stable or decrease despite continuation of the drug </li></ul><ul><li>Liver morphology: fatty liver </li></ul><ul><li>Direct hepatoxic effect </li></ul><ul><li>Liver injury may persist for months after discontinuation ( long half-life) </li></ul>
  17. 18. <ul><li>More common in children </li></ul><ul><li>Cholestatic type </li></ul><ul><li>Idiosyncratic reaction </li></ul><ul><li>Nausea, vomiting, fever, RUQ pain, jaundice, leukocytosis, elevated aminotransferases </li></ul><ul><li>Clinical improvement upon drug withdrawal </li></ul><ul><li>No evidence of CLD on follow up </li></ul>
  18. 19. <ul><li>Combination of estrogenic and progestational steroids; estrogen is primarily responsible </li></ul><ul><li>Intrahepatic cholestasis </li></ul><ul><li>Pruritus and jaundice </li></ul><ul><li>Susceptible patients: idiopathic jaundice of pregnancy, family history </li></ul><ul><li>Focal nodular hyperplasia, adenomas </li></ul>
  19. 20. <ul><li>Jin Bu Huan </li></ul><ul><li>Xiao chai hu tang </li></ul><ul><li>Senna </li></ul><ul><li>Mistletoe </li></ul><ul><li>Skull cap </li></ul><ul><li>Ma huang </li></ul><ul><li>Bee pollen </li></ul><ul><li>Valerian root </li></ul><ul><li>Kava </li></ul><ul><li>Caelandine </li></ul><ul><li>Impila </li></ul><ul><li>Herbal tea </li></ul>
  20. 21. <ul><li>Pyrrolizidine alkaloids may contaminate Chinese herbal meds  venoocclusive disease  sinusoidal hepatic vein obstruction </li></ul><ul><li>Active metabolites, which maybe potentiated by alcohol and drugs that stimulate cytochrome P450 </li></ul><ul><li>Alternative meds may also stimulate cytochrome P450  amplify the hepatotoxicity of drug hepatotoxins </li></ul>

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