Hepatotoxicity

Question 1

What is the main function of the liver?

Answer 1

Responsible for filtering blood and making bile.

Supports proper function of virtually all organs and tissues.

Question 2

What are the four sources from which the liver receives blood?

Answer 2

The liver receives blood from four sources.

Question 3

What is the main type of metabolism involved with the addition/removal of components to the blood and bile?

Answer 3

Protein metabolism.

Breakdown product of RBCs (heme) metabolism tints urine color and gives it a smell.

Question 4

What is a lobule?

Answer 4

The functional unit of the liver, consisting of a bunch of hepatocytes.

Question 5

What is the most common model of hepatic micro architecture?

Answer 5

Lobular model.

Question 6

What is an alternative type of liver model?

Answer 6

Acinar model.

Question 7

What is a Kupffer cell?

Answer 7

A macrophage in the liver that clears particulates.

Question 8

What is a hepatocyte?

Answer 8

A parenchymal liver cell that performs all functions ascribed to the liver.

Question 9

What is a dendritic cell?

Answer 9

A specialized type of monocyte that displays antigens on its cell surface.

Question 10

What is a stellate cell?

Answer 10

A neuron characterized by a radial, star-like distribution of dendrites, found in the space of Disse.

Question 11

What are cholangiocytes?

Answer 11

Epithelial cells of hepatic ductules that modify the composition of bile.

Question 12

What can cause stress and lead to toxicity in the liver?

Answer 12

Modulations/disruptions in liver function.

Question 13

What can alcohol abuse lead to in terms of liver function?

Answer 13

Alcohol abuse leads to deposition of collagen and differentiation of myofibroblasts in the space of Disse.

Question 14

What is the space of Disse?

Answer 14

The space between sinusoids and hepatocytes.

Question 15

What cell types are activated under liver stress?

Answer 15

Kupffer cells and stellate cells.

Question 16

What are functional liver units called?

Answer 16

Acini (acinus).

Question 17

How are functional liver units subdivided?

Answer 17

Into three zones: zone 1 (peri-lobular), zone 2 (mid-lobular), and zone 3 (centri-lobular).

Question 18

What is a sinusoid?

Answer 18

Cellular borders of blood that mix the blood.

Question 19

What specializes hepatocyte function along zones?

Answer 19

Differential enzyme expression.

Question 20

What are different areas of the acinus susceptible to?

Answer 20

Different toxins due to different cellular characteristics.

Question 21

What are inducers of zone 1 necrosis?

Answer 21

Allyl alcohol and phosphorus.

Question 22

What is zone 1 necrosis characterized by?

Answer 22

High levels of glutathione and oxygen, leading to O2 free radical induced necrosis.

Question 23

What are inducers of zone 3 necrosis?

Answer 23

Alpha-amanitin, acetaminophen, CCl3, chloroform, halothane.

Question 24

What is zone 3 necrosis characterized by?

Answer 24

High CYP2E1, high alcohol dehydrogenase, and low oxygen.

Question 25

Which zone is the most susceptible to damage?

Answer 25

Zone 3.

Question 26

Why is zone 3 most susceptible?

Answer 26

Due to increased risk of ATP depletion.

Question 27

What transporters do hepatocytes express?

Answer 27

OATPs, BSEP, MRP2, BCRP, MDR.

Question 28

What are bile acids?

Answer 28

Cholesterol derivatives.

Question 29

How much bile does the liver synthesize daily?

Answer 29

600-1000 mg.

Question 30

What is the total bile pool?

Answer 30

~3g, stored in the gallbladder.

Question 31

What is canalicular cholestasis?

Answer 31

Disruption in the production of biliary secretion.

Question 32

How can canalicular cholestasis be detected?

Answer 32

Through bloodwork for enzymes.

Question 33

What are clinical symptoms of canalicular cholestasis?

Answer 33

Jaundice and inflammation.

Question 34

What is jaundice?

Answer 34

Failure to break down bilirubin from hemoglobin.

Question 35

What hormones inhibit BSEP from the canalicular side?

Answer 35

Estrogen and progesterone.

Question 36

What drugs can inhibit BSEP?

Answer 36

Troglitazone and rifampicin.

Question 37

What triggers inflammatory/stress gene expression and liver damage?

Answer 37

Build-up of salt.

Question 38

What is apoptosis mediated cell death largely dependent on?

Answer 38

Death receptor dependent (extrinsic apoptotic pathway).

Question 39

What causes swelling of the liver?

Answer 39

Blockage of sinusoids, especially in zone 3.

Question 40

What happens when liver function declines?

Answer 40

Poor blood filtration.

Question 41

What can cause liver function decline?

Answer 41

Cytoskeletal changes in endothelium and collapse of space of Disse.

Question 42

What is veno-occlusive disease?

Answer 42

Cytoskeletal changes in endothelium and collapse of space of Disse.

Question 43

What can indicate early liver toxicity?

Answer 43

Cholangiocyte swelling.

Question 44

What is bile duct damage?

Answer 44

Ducts carry bile acids to the GI tract, lined by cholangiocytes.

Question 45

What is a sign of toxicity?

Answer 45

Initial cholangiocyte swelling.

Question 46

What chronic toxicity causes?

Answer 46

Biliary proliferation and fibrosis.

Question 47

What is vanishing bile duct syndrome?

Answer 47

Progressive destruction of intrahepatic bile ducts.

Question 48

What can cause vanishing bile duct syndrome?

Answer 48

Some antibiotics, anabolic steroids, contraceptive steroids, and carbamazepine.

Question 49

What do stressed cells activate?

Answer 49

Apoptotic or necrotic death pathways.

Question 50

What are the two bile-induced death pathways?

Answer 50

1. Mito-caspase 8-caspase 3-Bcl2 family proteins-cytochrome c release. 2. Fas-dependent classical (FADD)-DISC-cFLIP-caspase cascade.

Question 51

How do hydrophilic acids oppose homeostatic disturbances?

Answer 51

Using cAMP, PI3K, MAPK.

Question 52

How do hydrophobic acids induce apoptosis?

Answer 52

By cytokine storm followed by cell surface death-receptor mediated signaling.

Question 53

What are microcystin characteristics?

Answer 53

Cyanobacteria and environmental blooms.

Question 54

What is the pharmacokinetics of microcystin?

Answer 54

Taken up by OATPs, conjugated by glutathione.

Question 55

What does microcystin cause?

Answer 55

Phosphorylation of cytoskeletal proteins, leading to hepatocyte deformation.

Question 56

What happens at low doses of microcystin?

Answer 56

Inhibition of dynein motor protein affecting sub-cellular trafficking.

Question 57

What is acetaminophen (APAP) known for?

Answer 57

The most common cause of liver injury in Canada, USA, and UK.

Question 58

What does APAP cause?

Answer 58

Hepatotoxicity via cell death and fibrosis.

Question 59

What happens at therapeutic doses of APAP?

Answer 59

90% is conjugated and non-toxic.

Question 60

What causes APAP toxicity?

Answer 60

Saturation of glucuronidation and sulfation pathways at high doses.

Question 61

What does NAPQI facilitate?

Answer 61

Redox cycling and free radical generation.

Question 62

What happens once GSH is depleted?

Answer 62

Free radicals cause damage.

Question 63

What does NAC1 provide?

Answer 63

Sulfur for the PST reaction.

Question 64

What does NAC2 provide?

Answer 64

Cysteine to regenerate GSH.

Question 65

What does NAC3 do?

Answer 65

Substitutes for GSH.

Question 66

What does NAC4 prevent?

Answer 66

NAPQI toxicity.

Question 67

What does NAPQI covalently modify?

Answer 67

Proteins, especially in the mitochondria.

Question 68

What happens when MPTP opens?

Answer 68

Mitochondrial dysfunction occurs.

Question 69

What does mitochondrial dysfunction from APAP toxicity cause?

Answer 69

Apoptosis or necrosis depending on kinetics.

Question 70

What continues to spread injury to adjacent cells?

Answer 70

Release of DNAse 1 and calpains from ruptured cells.

Question 71

How can APAP toxicity be treated?

Answer 71

With n-acetylcysteine (NAC).

Question 72

What is chloroform?

Answer 72

Not an ultimate poison; can be reduced or oxidized.

Question 73

What does the oxidative pathway of chloroform involve?

Answer 73

Dechlorination to trichloromethanol and then to phosgene.

Question 74

What is phosgene?

Answer 74

Highly reactive and acetylates proteins, carbohydrates, and lipids.

Question 75

What does phosgene deplete?

Answer 75

GSH stores, inducing severe oxidative stress.

Question 76

What is steatosis?

Answer 76

Fat in stool, indicating liver failure.

Question 77

What does the reductive pathway of chloroform involve?

Answer 77

Dichloromethyl free radical labeling enzymes and phospholipids.

Question 78

What are the three stages of alcoholic liver disease?

Answer 78

1. Development of fatty liver. 2. Alcoholic hepatitis. 3. Cirrhosis.

Question 79

How does liver function decrease?

Answer 79

Through stages of alcoholic liver disease.

Question 80

What happens to excess acetate?

Answer 80

Converted to acetyl-CoA by thiokinase.