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PHAR 303 (toxicology) > Liver toxicology > Flashcards

Liver toxicology Flashcards

final exam

1
Q

functions of the liver

A
  1. protein synthesis (plasma proteins)
  2. metabolic functions
  3. bile production
  4. detoxicifcation
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2
Q

what can happen if the function of the liver is altered?

A
  1. excessive bleeding (no protein synthesis)
  2. hypoglycemia (low glucose metabolism)
  3. malnutrition (low bile production)
  4. diminished metabolism (of xenobiotics)
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3
Q

explain the blood supply of the liver.

A

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)

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4
Q

the basic unit of the liver

A

liver lobule

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5
Q

how is a liver lobule organized?

A
  • 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
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6
Q

what are the cell types in the liver lobule?

A
  1. hepatocyte
  2. endothelial cell
  3. Kupffer cells
  4. Ito cells
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7
Q

property of hepatocytes in liver lobule

A

One cell layer thick that are separated by liver sinusoids

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8
Q

what are liver sinusoids?

A

Channels between chords of hepatocytes where blood percolates on way to hepatic vein

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9
Q

organization of endothelial cells in liver lobules

A

line sinusoids

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10
Q

what are Kupffer cells

A

Hepatic macrophages engulf pathogens, cell debris and damaged blood cells

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11
Q

what are Ito cells

A

hepatic stellate cells that store vitamin A in the Space of Disse (space between hepatocyte and sinusoid

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12
Q

what is the smallest functional unit of the liver

A

hepatic acinus

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13
Q

what is the hepatic acinus (where is it located)

A

Oriented around the vascular system
- Located between 2 central veins and 2 portal triads

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14
Q

what do the zones in the liver acinus correspond to?

A

distance from blood supply (increasing distance from supply)

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15
Q

what are the zones of the liver acinus? (and their functions)

A
  • 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)
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16
Q

factors that influence liver toxicity

A
  • 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)
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17
Q

which zones (in acinus) are often the first affected? why?

A

zone 3 b/c of higher metabolism (so higher bioactivation)

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18
Q

injury of the liver depends on what?

A

(1) intensity of insult
(2) population of cells
affected and
(3) if exposure is chronic or acute

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19
Q

types of damage/injury that can occur

A
  1. Dysfunction: no cell damage, where toxicant blocks uptake, secretion, or bioactivation
  2. acute damage (kills hepatocytes): membrane integrity, mito. functions, cytoskeleton, transporters and enzymes
  3. Chronic damage: scar tissue in damaged area
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20
Q

most common type of zonal necrosis

A

zone 3 necrosis

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21
Q

Cholestasis definition

A

reduced or stopped bile flow due to a decrease in the volume of bile formed or an impaired secretion of specific solutes into bile

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22
Q

types of cholestasis

A

hepatocellular and canalicular

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23
Q

Hepatocellular cholestasis

A

bile accumulation in the cytoplasm of liver cells

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24
Q

Canalicular cholestasis

A

bile accumulation in the canaliculi

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25
Q

what is found in the serum during cholestasis

A
  • bile salts
  • bilirubin
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26
Q

what is bilirubin?

A

product of the catabolic process that breaks down heme

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27
Q

what causes jaundice?

A

bilirubin (yellowish) accumulates in skin and eyes

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28
Q

Potential mechanisms for cholestasis

A
  • 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)
29
Q

what is chlorpromazine?

A

medication used to treat schizophrenia and bipolar disorder

30
Q

what is a rare side effect of chlorpromazine?

A

cholestasis

31
Q

by which mechanism does chlorpromazine cause cholestasis?

A
  • impaired uptake
  • diminished contractility of canaliculus
32
Q

what is Cholangiodestructive cholestasis and how does this occur?

A
  • 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

33
Q

what is Paraquat?

A

widely used herbicide

34
Q

exposure to paraquat

A

mostly ingestion:
- deliberate
- accidental (can be easily mixed with beverages)

35
Q

what was done to reduce Paraquat exposure?

A

Form marketed now has:
– Blue dye
– Sharp odor
– Emetic agents

36
Q

effect of acute Paraquat exposure

A

cholestasis (minor) and lung disease

37
Q

Proposed mechanism of paraquat toxicity

A

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)

38
Q

fatty liver (hepatic steastosis) definition

A

the build-up of lipids (triglycerides) in the hepatocyte

39
Q

what is the fat content in a healthy vs fatty liver

A
  • normal: ≤ 5 % fat
  • fatty: ≥ 10% fat (can be as much as 50%)
40
Q

general pathways for steatosis

A
  1. influx of fatty acids (more breakdown from adipose or more from diet)
  2. increase de novo lipogenesis
  3. decrease TG secretion
  4. decrease fatty acid oxidation (aka breakdown)
41
Q

fatty liver is a common response to ______

A

hepatotoxicants

42
Q

what is carbon tetrachloride (properties)? where was it used?

A
  • 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)
43
Q

IARC classification of carbon tetrachloride

A

group 2B carcinogen

44
Q

Primary route of acute exposure of carbon tetrachloride

A
  • inhalation
  • accidental ingestion
45
Q

effects of carbon tetrachloride

A
  • Toxicant-associated fatty liver disease (TAFLD)
  • sometimes toxicant-associated steatohepatitis (TASH)
  • Kidney (less urine, kidney failure)
  • Nervous system (high levels; signs of intoxication)
46
Q

Synergy of risk of carbon tetrachloride with which other exposure? why?

A

Alcohol since increases CYP2E1

47
Q

mechanism of carbon tetrachloride

A
  • activated by CYP2E1
  • causes GSH depletion, lipid peroxidation, and disrupts lipid homeostasis/secretion (cannot secrete fatty acids)
  • all in liver
48
Q

which cancers can chronic alcohol consumption cause

A

upper digestive tract, liver, colorectal & breast cancer

49
Q

how ling does it take for alcoholic fatty liver disease (steatosis) to occur?

A
  • Occurs as quickly as 3 to 7 days excessive ingestion of ethanol
  • Almost everyone who drinks heavily for 12 weeks will develop fatty liver
50
Q

what is considered heavy drinking?

A

Males: 40-80 g/day (80g = 5 drinks)
Females: 20-40 g/day

51
Q

Alcoholic fatty liver (steatosis) is observed in up to __% of heavy drinkers

A

90%

52
Q

Alcoholic fatty liver progression (which steps are reversible)

A
  1. Steatosis (asymptomatic, reversible)
  2. Fibrosis (can be reversible)
  3. Cirrhosis (mostly irreversible)
  4. HCC
53
Q

Prerequisite for progression from Steatosis to fibrosis and cirrhosis

A
  • Fatty liver
  • Inflammatory cells (PMN)
  • Hepatocellular damage
54
Q

mechanism of Alcoholic hepatitis (steatohepatitis)

A

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

  1. this leads to oxidative stress and steatosis
  2. this then leads to cell death (necrosis, apoptosis) in zone 3
  3. also produces DAMPs and increases CYP2E1
55
Q

Histopathology of alcoholic liver disease- fibrosis

A
  • normal tissue is replaced by scar tissue
  • characterized by increased extracellular matrix (ECM) that scars the liver – collagen
56
Q

most effective treatment for fibrosis (alcoholic liver disease)

A

removal of the causative agent

57
Q

what are Myofibroblasts and what is their role in liver fibrosis?

A
  • 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
58
Q

Alcoholic Cirrhosis definition

A

Diffuse process characterized by fibrosis and conversion of normal liver architecture into structurally abnormal nodules
- is a pre-neoplastic lesion

59
Q

risk factor of hepatocellular carcinoma

A

cirrhosis (and therefore heavy alcohol consumption)

60
Q

what are some polymorphisms in ethanol metabolism enzymes?

A

ADH1B2 (40x more active) or ALDH22/2 (almost inactive) = Protective against alcohol dependence (causes flushing syndrome)

61
Q

properties of vinyl chloride

A
  • colorless gas with a mild sweet odor
  • evaporates easily
  • does not bioaccumulate
62
Q

IARC classification of vinyl chloride

A

group 1

63
Q

what can vinyl chloride cause?

A
  • HCC (VC and alcohol synergize)
  • hepatic angiosarcoma (extremely rare cancer)
64
Q

where does Hepatic angiosarcoma originate?

A

endothelial cells

65
Q

latency period of hepatic angiosarcoma

A

9-35 years (avg is 20 yrs)

66
Q

mechanism of toxicity of vinyl chloride

A
  • 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
67
Q

Acetaminophen Metabolism and toxicity

A

-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

68
Q

what happens when acetaminophen is taken with alcohol?

A
  • alcohol increases CYP2E1, which increases acetaminophen metabolism into its toxic metabolite
  • alcohol also depletes GSH, which sensitizes individuals to acetaminophen

PHAR 303 (toxicology) (14 decks)

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