Hepatic Toxicity

Question 1

Function of the liver

Answer 1

metabolic homeostasis for the whole body

Question 2

drug induced liver injury (DILI)

Answer 2

responsible for 5% of all hospital admissions, 50% of all acute liver failure

Question 3

what three levels are tested to measure liver toxicity?

Answer 3

serum levels of alanine aminotransferase (ALT)
serum levels of alkaline phosphatase (ALP)
serum levels of bilirubin

Question 4

serum levels of ALT, need to be what above the normal limit to indicate hepatocyte damage?

Answer 4

3X the normal upper limit

Question 5

serum levels of ALP, need to be what above the normal limit to indicate hepatocyte damage?

Answer 5

2X the normal upper limit

Question 6

serum levels of bilirubin, need to be what above the normal limit to indicate hepatocyte damage?

Answer 6

2X the normal upper limit

Question 7

3 reasons why the liver is susceptible to toxicity

Answer 7

1. 1st pass effect
2. exposure to high concentrations
3. major site of biotransformation

Question 8

main structural component of the liver is the

Answer 8

heptocyte

Question 9

the hepatic portal vein provides most of

Answer 9

the livers blood flow

Question 10

bile is a yellow fluid containing

Answer 10

bile acids, glutathione, phospholipids, cholesterol, bilirubin, proteins, metals, ions

Question 11

the formation of bile is specialized to what organ?

Answer 11

the liver!

Question 12

where is bile stored?

Answer 12

gall bladder

Question 13

canalicular lumen is the space formed by

Answer 13

specialized regions of plasma membrane between adjacent hepatocytes
well formed channels

Question 14

epithelial cells (2 kinds)

Answer 14

hepatocytes

bile duct epithelial cells

Question 15

non-parenchymal cells (3 kinds)

Answer 15

endothelial cells
kupffer cells
stellate cells

Question 16

endothelial cells line

Answer 16

sinusoids (capillary)

Question 17

kupffer cells are resident ____ of the liver

Answer 17

macrophages

Question 18

kupffer cells are found in what?

Answer 18

the lumen of th esinusoid

Question 19

kupffer function is to

Answer 19

ingest and degrade particulate matter

Question 20

stellate cells are located in

Answer 20

space of Disse

Question 21

stellate cells are a major site of vitamin

Answer 21

A storage

Question 22

stellate cells can synthesize and secrete

Answer 22

collagen when activated

Question 23

stellate cells are also ____ storing cells

Answer 23

FAT

Question 24

stellate cells can contribute to what disease?

Answer 24

fibrosis

Question 25

hepatocytes in different zones are

Answer 25

exposed to different microenvironment and are functionally different

Question 26

acetaminophen overdose is the most common cause of

Answer 26

acute liver failure

Question 27

what is the reactive metabolite formed in acetaminophen overdose??

Answer 27

NAPQI

Question 28

how is NAPQI formed?

Answer 28

via P450 metabolism

Question 29

if too much NAPQI is formed what happens

Answer 29

liver cell death via centrolobular necrosis

Question 30

canalicular cholestatsis is a decrease in volume of

Answer 30

bile formed/impaired secretion of specific solutes into bile

Question 31

canalicular cholestasis is characterized biochemically by elevated serum levels of compounds concentrated in

Answer 31

the bile - bilirubin/bile salts

Question 32

in bile duct damage, serum levels of bile acids and bilirubin are

Answer 32

elevated

Question 33

chronic administration of toxins to bile ducts causes

Answer 33

bile duct destruction and can lead to fibrosis

Question 34

sinusoidal damage can occur when the functional integrity of the sinusoid is compromised either by

Answer 34

dilation or blockade or by progressive destruction of endothelial wall

Question 35

what is the consequence of endothelial cell injury???

Answer 35

loss of barrier function

Question 36

what is the most common cause of fatty liver?

Answer 36

insulin resistance due to central obesity and sedentary lifestyle

Question 37

fatty liver is or isn’t reversible?

Answer 37

it is!!!!!

Question 38

primary cause of cirrhosis is

Answer 38

viral hepatitis

Question 39

characteristic feature of immune-mediated liver injury is the delay in onset of

Answer 39

injury/requirement for repeated exposure to drug and formation of antibodies against drug-modified hepatic proteins

Question 40

the hasten hypothesis says that reactive metabolites covalently bind to cellular proteins that drug modified proteins are taken up by

Answer 40

antigen presenting cells, cleaved to peptide fragments which are then presented to T-cells

Question 41

Danger Hypothesis says that damaged cells release ____ _____ that co-stimulate _____

Answer 41

danger signals

antigen presenting cells

Question 42

what is the leading cause for failure in clinical testing of drugs?

Answer 42

idiosyncratic hepatotoxicity