hepatotoxicity Flashcards
what are 5 major functions of the liver
- nutrient homeostasis
- filtration of particulates
- protein synthesis
- bioactivation and detoxification
- formation of bile and biliary secretion
what is 2 examples of nutrient homeostasis in the liver
glucose storage and synthesis, cholesterol uptake
what is 1 example of
filtration of particulates in the liver
products of intestinal bacteria
what is 3 examples of protein synthesis in the liver
clotting factors, albumin, transport proteins
what is 4 examples of bioactivation and detoxification in the liver
bilirubin, ammonia, steroid hormones, xenobiotics
what is 4 examples of formation of bile and biliary secretion
bile acid-dependent uptake of dietary lipids and vitamins, bilirubin and cholesterol, metals and xenobiotics (its okay if you dont really know)
what can happen with hypoalbuminemia
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)
what can happen if your liver is impaired and you make less clotting factors
more bleeding
what can happen if your liver is impaired and you get less bile acid-dependent uptake of dietary lipids and vitamins
fatty diarrhea, malnutrition, Vit E deficiency
what does the portal vein do
brings de oxygenated blood
what is in the portal trial
hepatic artery, portal vein, bile duct
which direction does blood flow in the acinus
from the portal venule and hepatic arteriole towards the central vein
which direction does bile flow in the acinus
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)
what is sinusoid
the main blood carrier vessel in the liver (like a capillary)
what is the order of cells going from the central vein to the hepatocytes
its just the central vein space, then endothelial cells, then the hepatocytes
what is special about the endothelial cells in the acinus + why
they have small gaps between then so that the hepatocytes have access to blood
what is the space of Disse
the small space between endothelial cells and hepatocytes
what are found in the space of
stellate cells
what do hepatocytes secrete + where does it go
Hepatocytes secrete bile into the canaliculi, and those secretions flow parallel to the sinusoids, but in the opposite direction that blood flows
how many zones in the liver
3
what is the first zone of the liver
periportal parenchyma
what is the second zone of the liver
midzone parenchyma
what is the third zone of the liver
centrilobar parenchyma
which zone has the highest oxygen levels
zone 1
which zone has the lowest oxygen levels
zone 3
which zone is by the portal vein
zone 1
which zone is by the bile duct
zone 1
which zone is by the hepatic vein
zone 3
which zone has high O2 free radical mediated necrosis
zone 1
which zone has high ethanol CCl4 and CYP2E1 metabolite mediated necrosis
Zone 3
which zone has high glucuronidation
Zone 3
which zone has high sulfation
Zone 3
which zone has high alcohol dehydrogenase
Zone 3
which zone has high CYP2E1
Zone 3
what kind of necrosis happens most in zone 1
o2 free radical mediated
what kind of necrosis happens most in zone 3
by ethanol, CCl4 and CYP2E1 metabolites
what does CCl4 do in zone 3
it gets metabolized into something toxic
what separates blood from hepatocytes
endothelial cells
how do substances pass through the endothelium
via gaps in the endothelium and into space of disse
what are stellate cells
fat storage cells, can promote fibrosis, immune
where are stellate cells
endothelium and into space of disse
what are kupffer cells
macrophages and also a source of free radicals
what are natural killer cells
lymphocytes that scavenge infected cells and tumor cells
where are kupffer cells
resident in the lumen of sinusoids (Dont leave the liver)
what is the primary purpose of kupffer cells
ingest and degrade particulate matter
what are 3 things that kupffer cells can release
TGF-B, MMP inhibitors, cytotoxins (like ROS RNS)
what does TGF-B do and how
induces fibrogenesis by stimulating stellate cells
what do MMP inhibitors do
prevent breakdown of fibrous tissue
what does MMP stand for
matrix metalloproteinases
what kind of cytotoxins do kupffer cells secrete
ROS RNS
what does activate of kupffer cells prior to exposure do + example
increases damage because activation with Vit A increases severity of CCl4 damage
what is something that can activate kupffer cells
vitamin A
what does vit A administration to kupffer cells before giving the mCCl4 do
increases damage severity
where are hepatic stellate cells found
in the space of disse between endothelial cells of sinusoids(blood vessel) and hepatocytes
what does stellate cells play a key role in
hepatic immunity
where is vit A stored
in hepatic stellate cells
what do hepatic stellate cells store
vitamin A
what happens visually/ structurally once hepatic stellate cells are exposed to a toxic insult
they change into a myofibroblast phenotype
what can hepatic stellate cells make and secrete once activated
collagen and other extracellular proteins
what is the major cell type in liver that is involved in fibrosis and why
hepatic stellate cells because they excrete collagen and other extracellular proteins when activated
besides collagen and other extracellular proteins, what else can stellate cells synthesize (3)
smooth muscle actin, TGF-B and MMP inhibitors
what are the 2 main cell types involved in laying down fibres (fibrosis) when insulted by chemicals
Kupffer and Stellate cells
what are the 2 main cell types that can secrete TGF-B
Kupffer and Stellate cells
what are the 2 main cell types that can secrete MMP inhibitors
Kupffer and Stellate cells
what is fibrosis
when collagen and smooth muscle is deposited in the space of Disse
what are 3 things that fibrosis can result in
constriction of sinusoids, disappearance of fenestrae, formation of non-functional nodes
why is there constriction of sinusoids with fibrosis
because more fibres are being layed down in the space of disse, so there is constriction there (where blood flows)
what happens to hepatocytes with constriction of sinusoids with fibrosis
there will be less access to blood :(
how does bile conjugate uptake work
OATPs are responsible, Na-independent
is bile conjugate uptake Na dependent or independent
independent
what kind of other things do OATPs take up
numerous drugs and hepatotoxins
where are cannaliculi
between hepatocytes
what is required to pump constituents into bile
ATP
what are 4 pumps that are found pumping things into the bile in the canaliculi
BSEP
BCRP
MDR
MRP2
what does BSEP stand for
bile salt export pump
what does MRP2 stand for
multi drug resistance protein
what does BCRP stand for
breast cancer resistant protein
what does MDR stand for
multi drug resistance
what does BSEP do
use ATP to pump conjugated bile acids into the cannaliculi
what does BCRP do
use ATP to pump bile acids and xenobiotics into the cannaliculi
what does MRP2 do
use ATP to pump glutathione and various metals into the cannaliculi
what does MDR do
use ATP to pump various bile consistuents and xenobiotics into the cannaliculi
what is vital in the excretion of xenobiotics + why
energy driven pumps because you have to pump against the gradient
what are bile acids derived from
steroid acids derived from cholesterol
what % of cholesterol goes into bile acid synthesis
50%
what is a conjugated bile acid
it has a taurine or glycine added to it to increase its solubility
why do bile acids conjugate with taurine or glycine
to increase its solubility
what is the primary action of bile
to solubilize fats
what is a major constituent of bile
bile acids
what is canalicular cholestasis
decrease in volume of bile formed and secreted or impaired secretion of specific solutes in bile
what are 2 main results of canalicular cholestasis
- jaundice
- inflammation and cell death of hepatocytes
how does canalicular cholestasis cause jaundice
bilirubin accumulates and colors the skin and eyes and urin
what is bilirubin
hemoglobin breakdown product which is normally excreted in bile
how is bilirubin usually excreted
in bile
what is bilirubin the breakdown product of
hemoglobin
how can canalicular cholestasis cause inflammation and cell death of hepatocytes
bile salts can become toxic to hepatocytes if not excreted into bile
how do you detect canalicular cholestasis
elevated serum levels of bile salts and bilirubin and presence of bile plugs in canalicular network
how do you get bile in the serum with canalicular cholestasis
because they leak out of hepatocytes and get into the blood
how do you get bile plugs with canalicular cholestasis
bile becomes super thick and plug between individual hepatocytes or within bile ducts
is toxin induces cholestasis transient or chronic
either
what 3 bad things is canalicular cholestasis associated with + small description
cell (hepatocyte) death, cell swelling (cause occlusion in sinusoids) and inflammation (immune cell influx to liver is no good)
what is often the cause of canalicular cholestasis
the expression or function of transporters in the basolateral membrane (facing the sinusoid) of hepatocytes and canalicular membranes
can there be a genetic component to canalicular cholestasis and why
yes because some people may have diff amounts of transporters or something
how does estrogen cause canalicular cholestasis
it inhibits BSEP from canalicular side after excretion by MRP2
what happens when bile acids accumulate in the liver
they trigger expression of proinflammatory genes in hepatocytes which causes liver damage
how does bile acid-induced cell death seem to occur
largely apoptotic(but some necrosis-immune activation), triggered by activation of death receptors on hepatocyte membranes
what is cholangiodestructive cholestasis
damage to bile ducts
what is cholestasis
decrease in bile flow due to impaired secretion by hepatocytes or to obstruction of bile flow through bile ducts
what are cholangiocytes
cells that line ducts
what do bile ducts do
they carry bile from the liver to the GI
does bile consistency change in cholangiodestructive cholestasis + why
no, bile isnt flowing cause there is channel damage
what can cause cholangiocyte swelling
a single dose of a toxic agent may initially cause swelling
what does chronic toxic administration do to cholangiocytes
cause biliary proliferation and fibrosis
what 3 things peak in the serum with cholangiodestructive cholestasis
alkaline phosphatase, bile salts and bilirubin
where is alkaline phosphatase usually found
in bile ducts
what 2 things peak in the serum with canalicular cholestasis
bile salts and bilirubin
why do you find bile salts and bilirubin in the blood with cholangiodestructive cholestasis
because they arent making it into the gall bladder
what are a few things that can cause permanent bile duct loss
antibiotics, anabolic steroids, contraceptive steroids, cabamazepine (anti convulsant)
what is vanishing bile duct syndrome
drug induced liver injury marked clinically by chronic cholestasis and loss of bile ducts
where are sinusoids and what do they do
channels between hepatocytes that transport blood throughout the liver
what is veno-occlusive disease
when sinusoidal blockage can cause the liver to swell with blood while the rest of the body goes into shock
what can happen with sinusoidal blockage
the liver to swell with blood while the rest of the body goes into shock
what can be related to sinusoidal damage
cytoskeletal changes in endothelium and collapse of Spase of Disse
what can cytoskeletal changes in endothelium and collapse of Spase of Disse lead to
entrapment of RBCs which can lead to blocake of the channels
what can indirectly cause cytoskeletal changes in endothelium
disruption of cytoskleleton like microcystin (indirect)
what kind of drugs may cause veno-occlusive disease
with high doses of acetaminophen, steroids, some pyrrolizidine alkaloids in plants, catechins (in herbal teas)
what can catechin cause
consumption can lead to destruction of the endothelium of the sinusoids
what is microcystin + general function
a toxin from cyanobacteria that affects proteins involved in turnover of the actin cytoskeleton
what are 2 specific things that microcystin does
- prevents disassembly of actin filaments
- effects microtubules
what is the effect of microcystin on hepatocytes
they distort and the canalicular lumen dilates, can lead to loss of function
what is cyanobacteria
blue green algae
where do cyanobacteria live
fresh and salt water
when do cyanobacteria live
mostly in late summer early fall
how is microcystin uptake
by OATPs
what doe OATP stand for
organic anion transporting polypeptides
how can microcystin be detox
with GSH conjugation
how is microcystin transporter out of cels
with P-gp
what does microcystin do to cytoskeletal proteins specifically + how
they cause hyperphosphorylation of skeletal proteins
by covalently binding to the catalytic subunit of serine/threonine protein phosphatases
what can happen to the cytoskeleton with microcystin
they form a central spiny aggregate
what happens with phosphorylation with microcystin generally
inhibits dephosphorylation
what does microcystin do to vesicular transport and how + what doses
it inhibits it and lower doses
by interfering with dynein, a transport protein which required phosphatases to function
what is dynein
a transport protein
what does dynein require to function
phosphatases
what do phosphatases do
remove phosphorylation
generally what does microcystin do at low doses
increases phosphorylated dynein so there is decreased secretion and export
generally what does microcystin do at high doses
deformation of hepatocyte
how does acetaminophen overdose cause severe hepatotoxicity
via cell death and fibrosis
what happens to acetaminophen at therapeutic doses
more than 90% is conjugated to become non toxic
what is the reactive metabolite of acetaminophen
N-acetylbenzoquinoneimine (NAPQI)
why do you get NAPQi at high doses
because glucuronidation and sulfation pathways are saturated at high doses - so depletion of GSH
what are the 2 type of acetaminophen conjugation reactions
to make glucuronide and sulfated acetaminophen products
are the glucuronide and sulfated products toxic
no
what happens if acetaminophen escapes normal detox conjugations and makes it to zone 3
then you get it conjugated with glutathione
what is the main toxic acetaminophen peoduct
NAPQI
what is the best way to reduce acetaminophen toxicity
give patient N-acetylcysteine
what are 4 things that N-acetylcysteine does to help with acetaminophen overdose
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
what are 2 main good things that happen when you add N-acetylcysteine
- prevents NAPQI formation
- increases capacity to detox
how does NAPQI do its toxicity
covalently binding to proteins esp in mitochondria
what is a critical first step in toxicity
covalently binding to proteins
what does NAPQI covalently binding to proteins in mitochondria cause
MPT pore opening and loss of mitochondrial function and cell death - apoptosis then necrosis
what is released from cells when they die from NAPQI + what does it do
Dnase-1 and calpains are released after membrane ruptures which can result in spread of injury to adjacent cells
what are calpains
calcium-activated proteases
what can make NAPQI damage even worse
concurrent use of green tea extracts
what are 2 things that further deplete GSH
fasting andd protein malnutrition
when do you know if you should give N-acetylcysteine to the patient
by using the acetaminophen nomogram
what are the 2 lines on the acetaminophen nomogram + how do they look (Slope) and which is on top
dashed line and solid line (treatment line)
downwards slope, dashed is above treatment
what does the dashed line mean
dashed line shows the relationship between blood level and hepatotoxicity based on clinical data (SO where toxicity occurs)
when do you give N-acetylcysteine in relation to the acetaminophen nomogram
if the patient is above the treatment line
why is the treatment line under the toxicity line
because you want to make sure treatment is given in more borderline situations, even if they arent toxicated
what are the axis of the acetaminophen nomogram
acetamin concentration and time
which line is the toxic line
the dashed line above the treatment line
