Liver toxicology Flashcards
final exam
functions of the liver
- protein synthesis (plasma proteins)
- metabolic functions
- bile production
- detoxicifcation
what can happen if the function of the liver is altered?
- excessive bleeding (no protein synthesis)
- hypoglycemia (low glucose metabolism)
- malnutrition (low bile production)
- diminished metabolism (of xenobiotics)
explain the blood supply of the liver.
The liver has a double blood supply
- ~ 70% of blood comes from hepatic portal vein
(Drains stomach & intestines and Is oxygen-poor but nutrient-rich)
- ~ 30% blood comes from hepatic artery:
(Is oxygen-rich)
Hepatic Portal system:
- two capillary beds connected by a vein (begins and ends in capillaries)
the basic unit of the liver
liver lobule
how is a liver lobule organized?
- central vein surrounded by hepatic portal vein, hepatic arteries, and a small branch of bile duct
- makes up the hepatic triad
- blood enters and exits via the sinusoids
what are the cell types in the liver lobule?
- hepatocyte
- endothelial cell
- Kupffer cells
- Ito cells
property of hepatocytes in liver lobule
One cell layer thick that are separated by liver sinusoids
what are liver sinusoids?
Channels between chords of hepatocytes where blood percolates on way to hepatic vein
organization of endothelial cells in liver lobules
line sinusoids
what are Kupffer cells
Hepatic macrophages engulf pathogens, cell debris and damaged blood cells
what are Ito cells
hepatic stellate cells that store vitamin A in the Space of Disse (space between hepatocyte and sinusoid
what is the smallest functional unit of the liver
hepatic acinus
what is the hepatic acinus (where is it located)
Oriented around the vascular system
- Located between 2 central veins and 2 portal triads
what do the zones in the liver acinus correspond to?
distance from blood supply (increasing distance from supply)
what are the zones of the liver acinus? (and their functions)
- Zone 1 (periportal): Closest to the arterioles; best oxygenated; higher glutathione (GSH); ammonia detoxification, fatty acid oxidation
- Zone 2: Intermediate/mid-lobular
- Zone 3 (perivenous/pericentral): Farthest from arterioles; least oxygenated; xenobiotic metabolism (higher CYP450s)
factors that influence liver toxicity
- zones that are affected (differently affected by toxicants)
- uptake and concentration (Fenestrations in the sinusoids enables close contact with hepatocytes)
- Activation of sinusoidal cells (Kupffer cells)
which zones (in acinus) are often the first affected? why?
zone 3 b/c of higher metabolism (so higher bioactivation)
injury of the liver depends on what?
(1) intensity of insult
(2) population of cells
affected and
(3) if exposure is chronic or acute
types of damage/injury that can occur
- Dysfunction: no cell damage, where toxicant blocks uptake, secretion, or bioactivation
- acute damage (kills hepatocytes): membrane integrity, mito. functions, cytoskeleton, transporters and enzymes
- Chronic damage: scar tissue in damaged area
most common type of zonal necrosis
zone 3 necrosis
Cholestasis definition
reduced or stopped bile flow due to a decrease in the volume of bile formed or an impaired secretion of specific solutes into bile
types of cholestasis
hepatocellular and canalicular
Hepatocellular cholestasis
bile accumulation in the cytoplasm of liver cells
Canalicular cholestasis
bile accumulation in the canaliculi
what is found in the serum during cholestasis
- bile salts
- bilirubin
what is bilirubin?
product of the catabolic process that breaks down heme
what causes jaundice?
bilirubin (yellowish) accumulates in skin and eyes
Potential mechanisms for cholestasis
- impaired uptake due to impaired expression/function of transporters (NTCP and/or OATP)
- diminished transcytosis
- impaired secretion
- diminished contractility of canaliculus
- leaky paracellular junctions (causes spillage, so impaired release)
- concentration of reactive species (damages cell)
what is chlorpromazine?
medication used to treat schizophrenia and bipolar disorder
what is a rare side effect of chlorpromazine?
cholestasis
by which mechanism does chlorpromazine cause cholestasis?
- impaired uptake
- diminished contractility of canaliculus
what is Cholangiodestructive cholestasis and how does this occur?
- Damage to the bile ducts that carry bile from the liver to the GI tract (either Intrahepatic bile ducts or biliary epithelium)
caused by lesions in the biliary tree:
- Bile duct obstruction (cell edema, inflammation)
- Can be acute (drugs = 1-6 months) or chronic
- Vanishing bile duct syndrome = loss of bile ducts
what is Paraquat?
widely used herbicide
exposure to paraquat
mostly ingestion:
- deliberate
- accidental (can be easily mixed with beverages)
what was done to reduce Paraquat exposure?
Form marketed now has:
– Blue dye
– Sharp odor
– Emetic agents
effect of acute Paraquat exposure
cholestasis (minor) and lung disease
Proposed mechanism of paraquat toxicity
increases ROS production through various pathways, causing mitochondrial injury and excessive autophagy. Leading to apoptosis and organ injury (in lung and kidney major, and liver minor)
fatty liver (hepatic steastosis) definition
the build-up of lipids (triglycerides) in the hepatocyte
what is the fat content in a healthy vs fatty liver
- normal: ≤ 5 % fat
- fatty: ≥ 10% fat (can be as much as 50%)
general pathways for steatosis
- influx of fatty acids (more breakdown from adipose or more from diet)
- increase de novo lipogenesis
- decrease TG secretion
- decrease fatty acid oxidation (aka breakdown)
fatty liver is a common response to ______
hepatotoxicants
what is carbon tetrachloride (properties)? where was it used?
- CCl4 is a clear liquid with a sweet smell that evaporates very easily
- Persistent environmental pollutant- stable
- Previously used in fire extinguishers, pesticides, insulating foams, dry cleaning solvent, cleaner, Freon production (refrigerators)
IARC classification of carbon tetrachloride
group 2B carcinogen
Primary route of acute exposure of carbon tetrachloride
- inhalation
- accidental ingestion
effects of carbon tetrachloride
- Toxicant-associated fatty liver disease (TAFLD)
- sometimes toxicant-associated steatohepatitis (TASH)
- Kidney (less urine, kidney failure)
- Nervous system (high levels; signs of intoxication)
Synergy of risk of carbon tetrachloride with which other exposure? why?
Alcohol since increases CYP2E1
mechanism of carbon tetrachloride
- activated by CYP2E1
- causes GSH depletion, lipid peroxidation, and disrupts lipid homeostasis/secretion (cannot secrete fatty acids)
- all in liver
which cancers can chronic alcohol consumption cause
upper digestive tract, liver, colorectal & breast cancer
how ling does it take for alcoholic fatty liver disease (steatosis) to occur?
- Occurs as quickly as 3 to 7 days excessive ingestion of ethanol
- Almost everyone who drinks heavily for 12 weeks will develop fatty liver
what is considered heavy drinking?
Males: 40-80 g/day (80g = 5 drinks)
Females: 20-40 g/day
Alcoholic fatty liver (steatosis) is observed in up to __% of heavy drinkers
90%
Alcoholic fatty liver progression (which steps are reversible)
- Steatosis (asymptomatic, reversible)
- Fibrosis (can be reversible)
- Cirrhosis (mostly irreversible)
- HCC
Prerequisite for progression from Steatosis to fibrosis and cirrhosis
- Fatty liver
- Inflammatory cells (PMN)
- Hepatocellular damage
mechanism of Alcoholic hepatitis (steatohepatitis)
1a. Alcohol dehydrogenase converts it to acetaldehyde
1b. ALDH: Aldehyde dehydrogenase converts it to acetate
2. acetaldehyde inhibits GSH, which increases ROS:
- ↓ PPARα – blocks fatty acid oxidation and export
- ↑ SREBP1c (sterol regulatory element-binding protein 1c) = lipogenesis
- this leads to oxidative stress and steatosis
- this then leads to cell death (necrosis, apoptosis) in zone 3
- also produces DAMPs and increases CYP2E1
Histopathology of alcoholic liver disease- fibrosis
- normal tissue is replaced by scar tissue
- characterized by increased extracellular matrix (ECM) that scars the liver – collagen
most effective treatment for fibrosis (alcoholic liver disease)
removal of the causative agent
what are Myofibroblasts and what is their role in liver fibrosis?
- activated form of Ito (aka stellate cells)
- TGF-B will activate macrophages, which will activate stellate cells, which will then Secrete collagens and other ECM proteins, leading to fibrosis
Alcoholic Cirrhosis definition
Diffuse process characterized by fibrosis and conversion of normal liver architecture into structurally abnormal nodules
- is a pre-neoplastic lesion
risk factor of hepatocellular carcinoma
cirrhosis (and therefore heavy alcohol consumption)
what are some polymorphisms in ethanol metabolism enzymes?
ADH1B2 (40x more active) or ALDH22/2 (almost inactive) = Protective against alcohol dependence (causes flushing syndrome)
properties of vinyl chloride
- colorless gas with a mild sweet odor
- evaporates easily
- does not bioaccumulate
IARC classification of vinyl chloride
group 1
what can vinyl chloride cause?
- HCC (VC and alcohol synergize)
- hepatic angiosarcoma (extremely rare cancer)
where does Hepatic angiosarcoma originate?
endothelial cells
latency period of hepatic angiosarcoma
9-35 years (avg is 20 yrs)
mechanism of toxicity of vinyl chloride
- at the sinusoidal level
- activated by CYP2E1, making CEO (chloroethylene oxide)
- can lead to DNA adduct and metabolic inactivation in the hepatocyte (but there are more repair mechanisms so much of the potential damage is avoided)
- can also go in the endothelial cells as CEO, causing DNA adducts, but here will cause damage and potentially angiosarcoma since has fewer repair mechanisms and higher replication rate
Acetaminophen Metabolism and toxicity
-metabolized by CYPs (including CYP2E1) into NAPQI, a toxic metabolite
- usually inactivated by GSH in the hepatocyte, leading to non-toxic conjugates that can be eliminated
- if taken at toxic doses, GSH is depleted, leading to Hepatocyte cell death
and Zone 3 necrosis within 72-96 hours
what happens when acetaminophen is taken with alcohol?
- alcohol increases CYP2E1, which increases acetaminophen metabolism into its toxic metabolite
- alcohol also depletes GSH, which sensitizes individuals to acetaminophen
