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Inhalation, Ingestion, parenteral administration
Industrial toxins (CCl4, yellow phosphorus)
Mushroom poisoning (Amenita, Galerina)
Pharmacologic agents
Direct toxic Carbon
tetrachloride Acetaminophen Halothane
Idiosyncratic
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
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
Cholestasis Fatty liver Hepatitis Mixed hepatitis/cholestasis Toxic (necrosis) Grnulomas
Methyl testosteroneErythromycinRifampinAmoxicillin-
clavulanic OxacillinClopidogrelIrbersartanNifedipineVerapamil
MethimazoleSulindacEzetimibeTamoxifenMestranolChlorpropamideChlorpromazine
Amiodarone Tertracycline (high dose IV) Valproic acid Antiviral protease inhibitors
(indinavir, ritonavir) Methorexate
HalothaneIsoniazid (INH)RifampinPyrazinamide (PZA)PhenytoinCarbamazineKetoconazoleFluconazoleItraconazoleMethyldopaCaptoprilLosartan
IbuprofenDiclofenacIndomethacinSulindacNifedipineVerapamilDiltiazemChlorothiazideTroglitazoneAcarboseAntiviral Protease inhibitors
(ritnavir, idinavir)
Amoxicillin/Clavulanic acid Trimethoprim/Sulfamethoxazole Azathioprine Nicotinic acid Lovastatin Ezetimibe
AcetaminophenCarbon tetrachlorideYellow phosphorusAmanita phalloidesDimethylformamide
Quinidine Sulfonamides Carbamazine Allopurinol
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
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
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
Idiosyncratic type Steven Johnson’s syndrome:
exfoliative dermatitis, fever, lymphadenopathy; leukocytosis, eosinopilia immune mediated hypersensitivity mechanism
Liver morphology: hepatitis-like picture (majority); cholestasis (rare)
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)
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
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
Jin Bu Huan Xiao chai hu tang Senna Mistletoe Skull cap Ma huang Bee pollen
Valerian root Kava Caelandine Impila Herbal tea
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