Hepatic Toxicity Flashcards
Function of the liver
metabolic homeostasis for the whole body
drug induced liver injury (DILI)
responsible for 5% of all hospital admissions, 50% of all acute liver failure
what three levels are tested to measure liver toxicity?
serum levels of alanine aminotransferase (ALT)
serum levels of alkaline phosphatase (ALP)
serum levels of bilirubin
serum levels of ALT, need to be what above the normal limit to indicate hepatocyte damage?
3X the normal upper limit
serum levels of ALP, need to be what above the normal limit to indicate hepatocyte damage?
2X the normal upper limit
serum levels of bilirubin, need to be what above the normal limit to indicate hepatocyte damage?
2X the normal upper limit
3 reasons why the liver is susceptible to toxicity
- 1st pass effect
- exposure to high concentrations
- major site of biotransformation
main structural component of the liver is the
heptocyte
the hepatic portal vein provides most of
the livers blood flow
bile is a yellow fluid containing
bile acids, glutathione, phospholipids, cholesterol, bilirubin, proteins, metals, ions
the formation of bile is specialized to what organ?
the liver!
where is bile stored?
gall bladder
canalicular lumen is the space formed by
specialized regions of plasma membrane between adjacent hepatocytes
well formed channels
epithelial cells (2 kinds)
hepatocytes
bile duct epithelial cells
non-parenchymal cells (3 kinds)
endothelial cells
kupffer cells
stellate cells
endothelial cells line
sinusoids (capillary)
kupffer cells are resident ____ of the liver
macrophages
kupffer cells are found in what?
the lumen of th esinusoid
kupffer function is to
ingest and degrade particulate matter
stellate cells are located in
space of Disse
stellate cells are a major site of vitamin
A storage
stellate cells can synthesize and secrete
collagen when activated
stellate cells are also ____ storing cells
FAT
stellate cells can contribute to what disease?
fibrosis
hepatocytes in different zones are
exposed to different microenvironment and are functionally different
acetaminophen overdose is the most common cause of
acute liver failure
what is the reactive metabolite formed in acetaminophen overdose??
NAPQI
how is NAPQI formed?
via P450 metabolism
if too much NAPQI is formed what happens
liver cell death via centrolobular necrosis
canalicular cholestatsis is a decrease in volume of
bile formed/impaired secretion of specific solutes into bile
canalicular cholestasis is characterized biochemically by elevated serum levels of compounds concentrated in
the bile - bilirubin/bile salts
in bile duct damage, serum levels of bile acids and bilirubin are
elevated
chronic administration of toxins to bile ducts causes
bile duct destruction and can lead to fibrosis
sinusoidal damage can occur when the functional integrity of the sinusoid is compromised either by
dilation or blockade or by progressive destruction of endothelial wall
what is the consequence of endothelial cell injury???
loss of barrier function
what is the most common cause of fatty liver?
insulin resistance due to central obesity and sedentary lifestyle
fatty liver is or isn’t reversible?
it is!!!!!
primary cause of cirrhosis is
viral hepatitis
characteristic feature of immune-mediated liver injury is the delay in onset of
injury/requirement for repeated exposure to drug and formation of antibodies against drug-modified hepatic proteins
the hasten hypothesis says that reactive metabolites covalently bind to cellular proteins that drug modified proteins are taken up by
antigen presenting cells, cleaved to peptide fragments which are then presented to T-cells
Danger Hypothesis says that damaged cells release ____ _____ that co-stimulate _____
danger signals
antigen presenting cells
what is the leading cause for failure in clinical testing of drugs?
idiosyncratic hepatotoxicity
