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