: some property of the drug renders it toxic in a predictable, dose-dependant way; there is a high incidence in exposed people; animal models can reproduce the injury; the injury effects certain regions of the liver
direct
: physiochemical injury to cell; destroys structural basis of metabolism (physical injury Þ metabolic injury)
i.e. phosphorus
indirect
: interference with metabolism, excretion, or modification of a metabolic pathway leads to structural injury (metabolic injury Þ physical injury) – acetominophen
Idiosyncratic
: injury is produced only in susceptible people; non-dose dependant; low incidence; often a delayed response; cannot be reproduced in animals; diffuse hepatic injury
may be characterized by either generalized or specific hypersensitivity
generalized hypersensitivity is characterized by fever, rash, eosinophilia, rechallenge effect
often caused by a metabolic aberration: an enzymatic abnormality produces a toxin that is not normally produced (i.e. isoniazid toxicity)
intrinsic and idiosyncratic toxicity are often overlapping and some responses may be a combination of both
Cellular Mechanisms
Intrinsic toxicity
most drugs are metabolized through the P-450 route; could lead to either free radicals or electrophiles
electrophilic intermediate
(from oxidation) Þ covalent binding to macromolecules Þ impaired function
eletrophiles are normally detoxified by glutathione via glutathione S-transferases
GSH depletion
Þ covalent binding to other proteins
some electrophiles can completely bypass the GSH pathway
Þ highly reactive and bad
free radical production
(from oxidation or reduction)
results from competition of the drug with oxygen for free electrons; if the drug wins it becomes a radical
free radicals
Þ lipid peroxidation Þ membrane damage Þ loss of structural integrity
free radicals
Þ covalent binding to proteins Þ altered funcion
Idiosyncratic Toxicity
neoantigens produced by the above mechanisms trigger an immune response
General
damage to systems that maintain ion balance, cell volume, pH
damage to lysosomal membranes with release of hydrolytic enzymes
disrupted Ca homeostasis
Þ cytoskeleton disruption
Histology of Liver Toxicity - acute
Cytotoxic injury
: target is mainly hepatocytes;
necroinflammatory: easily confused with acute viral hepatitis; examples are halothane and isoniazid
steatosis: fatty infiltration may be micro- or macro-vescicular (micro: tetracycline; macro: alcohol)
manifests as high transaminase levels; only slightly raised alkaline phosphatase levels
recovery is often rapid after discontinuing the drugs
Cholestatic injury
: mostly spares the hepatocytes, but blocks the flow of bile (mainly bile canaliculae)
cholangiolitic
: cholestasis accompanied by inflammation in triad area
canalicular
: cholestasis without inflammation; see bile pigments trapped in hepatocytes and canaliculae
manifests as high alkaline phosphatase levels; only slightly raised transaminases
recovery may be slow even after discontinuation of the drug
Mixed forms
: i.e. PAS and sulfonaminde toxicity Þ cytotoxic and cholestatic injury
most hepatotoxicity mechanisms lie on a spectrum of cytotoxic and cholestatic injury
Halothane
: liver injury and failure after multiple anesthesias; obese, elderly females more at risk Þ fat sequestering
Chlorpromazine
(cholangiolitic): causes cholestasis (1-2%) via free radical mediated inhibition of bile flow; 1-2 wk latency
Tetracycline
(interference with metabolism): dose-related inhibition of lipid transport Þ micro and macro vesicular steatosis; preg, renal disease at risk
Acetaminophen
: normal metabolism through glucuronidase (conjugation); some activation to toxic electrophile NAPQ1 via P-450 followed by glutathione detox; high dose, alcoholism, cimetidine lead to more P-450 metabolism and greater production of the toxin; glutathione depleted Þ fulminant liver failure (2 - 3 day latency)
characterized by huge transaminases, centrilobular necrosis
Isoniazid
: extrinsic, idiosyncratic toxicity; TB drug causes increased transaminases in 10% of patients (most asymptomatic); latency is 3 months, but damage starts in 1-4 weeks; rapid resolution on discontinuation
Alcohol
: chronic use induces P-450 Þ increases toxic effects of some drugs chronic alcohol use does not: deplete GSH, induce tissue hypoxia, increase lipid peroxidation