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PMCOL 303 > hepatotoxicity > Flashcards

hepatotoxicity Flashcards

1
Q

what are 5 major functions of the liver

A
  • nutrient homeostasis
  • filtration of particulates
  • protein synthesis
  • bioactivation and detoxification
  • formation of bile and biliary secretion
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2
Q

what is 2 examples of nutrient homeostasis in the liver

A

glucose storage and synthesis, cholesterol uptake

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3
Q

what is 1 example of

filtration of particulates in the liver

A

products of intestinal bacteria

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4
Q

what is 3 examples of protein synthesis in the liver

A

clotting factors, albumin, transport proteins

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5
Q

what is 4 examples of bioactivation and detoxification in the liver

A

bilirubin, ammonia, steroid hormones, xenobiotics

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6
Q

what is 4 examples of formation of bile and biliary secretion

A

bile acid-dependent uptake of dietary lipids and vitamins, bilirubin and cholesterol, metals and xenobiotics (its okay if you dont really know)

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7
Q

what can happen with hypoalbuminemia

A

A decrease in osmotic pressure due to a low albumin level allows fluid to leak out from the interstitial spaces into the peritoneal cavity, producing ascites (fluid build up in abdomen)

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8
Q

what can happen if your liver is impaired and you make less clotting factors

A

more bleeding

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9
Q

what can happen if your liver is impaired and you get less bile acid-dependent uptake of dietary lipids and vitamins

A

fatty diarrhea, malnutrition, Vit E deficiency

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10
Q

what does the portal vein do

A

brings de oxygenated blood

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11
Q

what is in the portal trial

A

hepatic artery, portal vein, bile duct

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12
Q

which direction does blood flow in the acinus

A

from the portal venule and hepatic arteriole towards the central vein

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13
Q

which direction does bile flow in the acinus

A

from the central vein towards the portal venule and hepatic arteriole (portal trial, goes from the middle which is the central vein to the outside of the lobe)

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14
Q

what is sinusoid

A

the main blood carrier vessel in the liver (like a capillary)

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15
Q

what is the order of cells going from the central vein to the hepatocytes

A

its just the central vein space, then endothelial cells, then the hepatocytes

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16
Q

what is special about the endothelial cells in the acinus + why

A

they have small gaps between then so that the hepatocytes have access to blood

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17
Q

what is the space of Disse

A

the small space between endothelial cells and hepatocytes

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18
Q

what are found in the space of

A

stellate cells

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19
Q

what do hepatocytes secrete + where does it go

A

Hepatocytes secrete bile into the canaliculi, and those secretions flow parallel to the sinusoids, but in the opposite direction that blood flows

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20
Q

how many zones in the liver

A

3

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21
Q

what is the first zone of the liver

A

periportal parenchyma

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22
Q

what is the second zone of the liver

A

midzone parenchyma

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23
Q

what is the third zone of the liver

A

centrilobar parenchyma

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24
Q

which zone has the highest oxygen levels

A

zone 1

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25
Q

which zone has the lowest oxygen levels

A

zone 3

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26
Q

which zone is by the portal vein

A

zone 1

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27
Q

which zone is by the bile duct

A

zone 1

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28
Q

which zone is by the hepatic vein

A

zone 3

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29
Q

which zone has high O2 free radical mediated necrosis

A

zone 1

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30
Q

which zone has high ethanol CCl4 and CYP2E1 metabolite mediated necrosis

A

Zone 3

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31
Q

which zone has high glucuronidation

A

Zone 3

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32
Q

which zone has high sulfation

A

Zone 3

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33
Q

which zone has high alcohol dehydrogenase

A

Zone 3

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34
Q

which zone has high CYP2E1

A

Zone 3

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35
Q

what kind of necrosis happens most in zone 1

A

o2 free radical mediated

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36
Q

what kind of necrosis happens most in zone 3

A

by ethanol, CCl4 and CYP2E1 metabolites

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37
Q

what does CCl4 do in zone 3

A

it gets metabolized into something toxic

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38
Q

what separates blood from hepatocytes

A

endothelial cells

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39
Q

how do substances pass through the endothelium

A

via gaps in the endothelium and into space of disse

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40
Q

what are stellate cells

A

fat storage cells, can promote fibrosis, immune

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41
Q

where are stellate cells

A

endothelium and into space of disse

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42
Q

what are kupffer cells

A

macrophages and also a source of free radicals

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43
Q

what are natural killer cells

A

lymphocytes that scavenge infected cells and tumor cells

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44
Q

where are kupffer cells

A

resident in the lumen of sinusoids (Dont leave the liver)

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45
Q

what is the primary purpose of kupffer cells

A

ingest and degrade particulate matter

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46
Q

what are 3 things that kupffer cells can release

A

TGF-B, MMP inhibitors, cytotoxins (like ROS RNS)

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47
Q

what does TGF-B do and how

A

induces fibrogenesis by stimulating stellate cells

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48
Q

what do MMP inhibitors do

A

prevent breakdown of fibrous tissue

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49
Q

what does MMP stand for

A

matrix metalloproteinases

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50
Q

what kind of cytotoxins do kupffer cells secrete

A

ROS RNS

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51
Q

what does activate of kupffer cells prior to exposure do + example

A

increases damage because activation with Vit A increases severity of CCl4 damage

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52
Q

what is something that can activate kupffer cells

A

vitamin A

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53
Q

what does vit A administration to kupffer cells before giving the mCCl4 do

A

increases damage severity

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54
Q

where are hepatic stellate cells found

A

in the space of disse between endothelial cells of sinusoids(blood vessel) and hepatocytes

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55
Q

what does stellate cells play a key role in

A

hepatic immunity

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56
Q

where is vit A stored

A

in hepatic stellate cells

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57
Q

what do hepatic stellate cells store

A

vitamin A

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58
Q

what happens visually/ structurally once hepatic stellate cells are exposed to a toxic insult

A

they change into a myofibroblast phenotype

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59
Q

what can hepatic stellate cells make and secrete once activated

A

collagen and other extracellular proteins

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60
Q

what is the major cell type in liver that is involved in fibrosis and why

A

hepatic stellate cells because they excrete collagen and other extracellular proteins when activated

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61
Q

besides collagen and other extracellular proteins, what else can stellate cells synthesize (3)

A

smooth muscle actin, TGF-B and MMP inhibitors

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62
Q

what are the 2 main cell types involved in laying down fibres (fibrosis) when insulted by chemicals

A

Kupffer and Stellate cells

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63
Q

what are the 2 main cell types that can secrete TGF-B

A

Kupffer and Stellate cells

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64
Q

what are the 2 main cell types that can secrete MMP inhibitors

A

Kupffer and Stellate cells

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65
Q

what is fibrosis

A

when collagen and smooth muscle is deposited in the space of Disse

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66
Q

what are 3 things that fibrosis can result in

A

constriction of sinusoids, disappearance of fenestrae, formation of non-functional nodes

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67
Q

why is there constriction of sinusoids with fibrosis

A

because more fibres are being layed down in the space of disse, so there is constriction there (where blood flows)

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68
Q

what happens to hepatocytes with constriction of sinusoids with fibrosis

A

there will be less access to blood :(

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69
Q

how does bile conjugate uptake work

A

OATPs are responsible, Na-independent

70
Q

is bile conjugate uptake Na dependent or independent

A

independent

71
Q

what kind of other things do OATPs take up

A

numerous drugs and hepatotoxins

72
Q

where are cannaliculi

A

between hepatocytes

73
Q

what is required to pump constituents into bile

A

ATP

74
Q

what are 4 pumps that are found pumping things into the bile in the canaliculi

A

BSEP
BCRP
MDR
MRP2

75
Q

what does BSEP stand for

A

bile salt export pump

76
Q

what does MRP2 stand for

A

multi drug resistance protein

77
Q

what does BCRP stand for

A

breast cancer resistant protein

78
Q

what does MDR stand for

A

multi drug resistance

79
Q

what does BSEP do

A

use ATP to pump conjugated bile acids into the cannaliculi

80
Q

what does BCRP do

A

use ATP to pump bile acids and xenobiotics into the cannaliculi

81
Q

what does MRP2 do

A

use ATP to pump glutathione and various metals into the cannaliculi

82
Q

what does MDR do

A

use ATP to pump various bile consistuents and xenobiotics into the cannaliculi

83
Q

what is vital in the excretion of xenobiotics + why

A

energy driven pumps because you have to pump against the gradient

84
Q

what are bile acids derived from

A

steroid acids derived from cholesterol

85
Q

what % of cholesterol goes into bile acid synthesis

A

50%

86
Q

what is a conjugated bile acid

A

it has a taurine or glycine added to it to increase its solubility

87
Q

why do bile acids conjugate with taurine or glycine

A

to increase its solubility

88
Q

what is the primary action of bile

A

to solubilize fats

89
Q

what is a major constituent of bile

A

bile acids

90
Q

what is canalicular cholestasis

A

decrease in volume of bile formed and secreted or impaired secretion of specific solutes in bile

91
Q

what are 2 main results of canalicular cholestasis

A
  • jaundice

- inflammation and cell death of hepatocytes

92
Q

how does canalicular cholestasis cause jaundice

A

bilirubin accumulates and colors the skin and eyes and urin

93
Q

what is bilirubin

A

hemoglobin breakdown product which is normally excreted in bile

94
Q

how is bilirubin usually excreted

A

in bile

95
Q

what is bilirubin the breakdown product of

A

hemoglobin

96
Q

how can canalicular cholestasis cause inflammation and cell death of hepatocytes

A

bile salts can become toxic to hepatocytes if not excreted into bile

97
Q

how do you detect canalicular cholestasis

A

elevated serum levels of bile salts and bilirubin and presence of bile plugs in canalicular network

98
Q

how do you get bile in the serum with canalicular cholestasis

A

because they leak out of hepatocytes and get into the blood

99
Q

how do you get bile plugs with canalicular cholestasis

A

bile becomes super thick and plug between individual hepatocytes or within bile ducts

100
Q

is toxin induces cholestasis transient or chronic

A

either

101
Q

what 3 bad things is canalicular cholestasis associated with + small description

A

cell (hepatocyte) death, cell swelling (cause occlusion in sinusoids) and inflammation (immune cell influx to liver is no good)

102
Q

what is often the cause of canalicular cholestasis

A

the expression or function of transporters in the basolateral membrane (facing the sinusoid) of hepatocytes and canalicular membranes

103
Q

can there be a genetic component to canalicular cholestasis and why

A

yes because some people may have diff amounts of transporters or something

104
Q

how does estrogen cause canalicular cholestasis

A

it inhibits BSEP from canalicular side after excretion by MRP2

105
Q

what happens when bile acids accumulate in the liver

A

they trigger expression of proinflammatory genes in hepatocytes which causes liver damage

106
Q

how does bile acid-induced cell death seem to occur

A

largely apoptotic(but some necrosis-immune activation), triggered by activation of death receptors on hepatocyte membranes

107
Q

what is cholangiodestructive cholestasis

A

damage to bile ducts

108
Q

what is cholestasis

A

decrease in bile flow due to impaired secretion by hepatocytes or to obstruction of bile flow through bile ducts

109
Q

what are cholangiocytes

A

cells that line ducts

110
Q

what do bile ducts do

A

they carry bile from the liver to the GI

111
Q

does bile consistency change in cholangiodestructive cholestasis + why

A

no, bile isnt flowing cause there is channel damage

112
Q

what can cause cholangiocyte swelling

A

a single dose of a toxic agent may initially cause swelling

113
Q

what does chronic toxic administration do to cholangiocytes

A

cause biliary proliferation and fibrosis

114
Q

what 3 things peak in the serum with cholangiodestructive cholestasis

A

alkaline phosphatase, bile salts and bilirubin

115
Q

where is alkaline phosphatase usually found

A

in bile ducts

116
Q

what 2 things peak in the serum with canalicular cholestasis

A

bile salts and bilirubin

117
Q

why do you find bile salts and bilirubin in the blood with cholangiodestructive cholestasis

A

because they arent making it into the gall bladder

118
Q

what are a few things that can cause permanent bile duct loss

A

antibiotics, anabolic steroids, contraceptive steroids, cabamazepine (anti convulsant)

119
Q

what is vanishing bile duct syndrome

A

drug induced liver injury marked clinically by chronic cholestasis and loss of bile ducts

120
Q

where are sinusoids and what do they do

A

channels between hepatocytes that transport blood throughout the liver

121
Q

what is veno-occlusive disease

A

when sinusoidal blockage can cause the liver to swell with blood while the rest of the body goes into shock

122
Q

what can happen with sinusoidal blockage

A

the liver to swell with blood while the rest of the body goes into shock

123
Q

what can be related to sinusoidal damage

A

cytoskeletal changes in endothelium and collapse of Spase of Disse

124
Q

what can cytoskeletal changes in endothelium and collapse of Spase of Disse lead to

A

entrapment of RBCs which can lead to blocake of the channels

125
Q

what can indirectly cause cytoskeletal changes in endothelium

A

disruption of cytoskleleton like microcystin (indirect)

126
Q

what kind of drugs may cause veno-occlusive disease

A

with high doses of acetaminophen, steroids, some pyrrolizidine alkaloids in plants, catechins (in herbal teas)

127
Q

what can catechin cause

A

consumption can lead to destruction of the endothelium of the sinusoids

128
Q

what is microcystin + general function

A

a toxin from cyanobacteria that affects proteins involved in turnover of the actin cytoskeleton

129
Q

what are 2 specific things that microcystin does

A
  • prevents disassembly of actin filaments

- effects microtubules

130
Q

what is the effect of microcystin on hepatocytes

A

they distort and the canalicular lumen dilates, can lead to loss of function

131
Q

what is cyanobacteria

A

blue green algae

132
Q

where do cyanobacteria live

A

fresh and salt water

133
Q

when do cyanobacteria live

A

mostly in late summer early fall

134
Q

how is microcystin uptake

A

by OATPs

135
Q

what doe OATP stand for

A

organic anion transporting polypeptides

136
Q

how can microcystin be detox

A

with GSH conjugation

137
Q

how is microcystin transporter out of cels

A

with P-gp

138
Q

what does microcystin do to cytoskeletal proteins specifically + how

A

they cause hyperphosphorylation of skeletal proteins

by covalently binding to the catalytic subunit of serine/threonine protein phosphatases

139
Q

what can happen to the cytoskeleton with microcystin

A

they form a central spiny aggregate

140
Q

what happens with phosphorylation with microcystin generally

A

inhibits dephosphorylation

141
Q

what does microcystin do to vesicular transport and how + what doses

A

it inhibits it and lower doses

by interfering with dynein, a transport protein which required phosphatases to function

142
Q

what is dynein

A

a transport protein

143
Q

what does dynein require to function

A

phosphatases

144
Q

what do phosphatases do

A

remove phosphorylation

145
Q

generally what does microcystin do at low doses

A

increases phosphorylated dynein so there is decreased secretion and export

146
Q

generally what does microcystin do at high doses

A

deformation of hepatocyte

147
Q

how does acetaminophen overdose cause severe hepatotoxicity

A

via cell death and fibrosis

148
Q

what happens to acetaminophen at therapeutic doses

A

more than 90% is conjugated to become non toxic

149
Q

what is the reactive metabolite of acetaminophen

A

N-acetylbenzoquinoneimine (NAPQI)

150
Q

why do you get NAPQi at high doses

A

because glucuronidation and sulfation pathways are saturated at high doses - so depletion of GSH

151
Q

what are the 2 type of acetaminophen conjugation reactions

A

to make glucuronide and sulfated acetaminophen products

152
Q

are the glucuronide and sulfated products toxic

A

no

153
Q

what happens if acetaminophen escapes normal detox conjugations and makes it to zone 3

A

then you get it conjugated with glutathione

154
Q

what is the main toxic acetaminophen peoduct

A

NAPQI

155
Q

what is the best way to reduce acetaminophen toxicity

A

give patient N-acetylcysteine

156
Q

what are 4 things that N-acetylcysteine does to help with acetaminophen overdose

A

1-provides a sulfur for sulfation reaction
2-provides cysteine for rate limiting reaction in GSH synthesis
3-may act as a GST substitute (it has sulfhydryl group)
4-prevents cellular toxicity through a number of mechanisms

157
Q

what are 2 main good things that happen when you add N-acetylcysteine

A
  • prevents NAPQI formation

- increases capacity to detox

158
Q

how does NAPQI do its toxicity

A

covalently binding to proteins esp in mitochondria

159
Q

what is a critical first step in toxicity

A

covalently binding to proteins

160
Q

what does NAPQI covalently binding to proteins in mitochondria cause

A

MPT pore opening and loss of mitochondrial function and cell death - apoptosis then necrosis

161
Q

what is released from cells when they die from NAPQI + what does it do

A

Dnase-1 and calpains are released after membrane ruptures which can result in spread of injury to adjacent cells

162
Q

what are calpains

A

calcium-activated proteases

163
Q

what can make NAPQI damage even worse

A

concurrent use of green tea extracts

164
Q

what are 2 things that further deplete GSH

A

fasting andd protein malnutrition

165
Q

when do you know if you should give N-acetylcysteine to the patient

A

by using the acetaminophen nomogram

166
Q

what are the 2 lines on the acetaminophen nomogram + how do they look (Slope) and which is on top

A

dashed line and solid line (treatment line)

downwards slope, dashed is above treatment

167
Q

what does the dashed line mean

A

dashed line shows the relationship between blood level and hepatotoxicity based on clinical data (SO where toxicity occurs)

168
Q

when do you give N-acetylcysteine in relation to the acetaminophen nomogram

A

if the patient is above the treatment line

169
Q

why is the treatment line under the toxicity line

A

because you want to make sure treatment is given in more borderline situations, even if they arent toxicated

170
Q

what are the axis of the acetaminophen nomogram

A

acetamin concentration and time

171
Q

which line is the toxic line

A

the dashed line above the treatment line

PMCOL 303 (25 decks)

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