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I&I WC1 > Hepatology > Flashcards

Hepatology Flashcards

1
Q

How many segments and lobules does the liver contain?

A

8 segments, ~100 lobules

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2
Q

What is the function of sinusoids in the liver?

A

Slow blood flow, allowing hepatocytes to get in contact with blood

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3
Q

True or false: hepatocytes directly contact bloods in the sinusoids

A

False; they are seperated by endothelial cells and sinusoidal cells

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4
Q

What is the space of Disse? Which cell types can be found here? (2)

A

Perisinusoidal space -> contains hepatic stellate cells & Kupffer cells

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5
Q

What are the metabolic functions of the liver? (7)

A
  1. Storage of nutrients
  2. Gluconeogenesis
  3. Deamination of amino acids
  4. Production of non-essential amino acids
  5. Fatty acid oxidation
  6. Production of cholesterol & lipoproteins
  7. Production of phospholipids
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6
Q

How is cholesterol excreted by the liver?

A

As bile salts

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7
Q

Which important groups of factors are synthesized by the liver? (5)

A
  1. Albumin
  2. Coagulation factors
  3. CRP
  4. Complement proteins
  5. Soluble PRRs
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8
Q

What is CRP? When is it released?

A

Pentraxin family member, released when IL-6 is produced. Binds lipids on bacterial surfaces and activates the classical complement pathway, causing bacteriolysis

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9
Q

What is LBP? What is its function?

A

Acute phase protein that binds LPS in circulation and transfers it to CD14 -> supports binding of LPS to TLR4

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10
Q

What is the function of soluble CD14, secreted by the liver?

A

Supports binding of LPS to TLR4 in case of absence of membrane-bound CD14

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11
Q

What should the liver be tolerogenic towards?

A

Food proteins & (endo)toxins

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12
Q

In which situations does unwanted hepatic tolerance occur? (3)

A
  1. HBV/HCV
  2. Plasmodium sporozoite
  3. Tumour metastases
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13
Q

What does the liver have immunity against?

A
  1. HAV
  2. HBV (early stages)
  3. Many bacterial species
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14
Q

What is the unique property of the liver when it comes to LTx?

A

HLA matching is not required due to its tolerogenic nature
LTx also confers protection against rejection of other solid organs from the same donor

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15
Q

Which immune cells can be found in the liver? (7)

A
  1. Kupffer cells -> antigen-presenting cells
  2. DCs
  3. Liver sinusoidal endothelial cells (LSEC)
  4. NK-cells
  5. NK T-cells
  6. Regular T- and B-cells
  7. Hepatic stellate cells
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16
Q

What is the function of hepatic stellate cells?

A

Vitamin A storage

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17
Q

What is the function of LSECs?

A

To remove waste products from blood and to capture pathogens, proteins and toxins from blood

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18
Q

How do LSECs capture antigens?

A

Scavenger receptors and carbohydrate receptors

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19
Q

LSECs can act as APCs. Which type of MHC do they use? Are they mainly tolerogenic or immunogenic?

A

Both MHCI/MHCII, mainly tolerogenic through low-level activation and secretion of anti-inflammatory cytokines

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20
Q

What is the function of Kupffer cells?

A

Tissue-resident macrophages -> phagocytose and degrade particulate materials from blood

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21
Q

Why do Kupffer cells express FcR?

A

Allows for clearaence of immune complexes

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22
Q

Why do Kupffer cells express complement receptors?

A

Clearance of C3b-coated bacteria

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23
Q

Why do Kupffer cells express TLR4?

A

Clearance of LPS from portal blood

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24
Q

Kupffer cells are mainly [tolerogenic/immunogenic] APCs?

A

Tolerogenic -> intermediate MHCII/costimulation & suppression of T-cell activation, induction of Tregs

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25
Q

How are Kupffer cells activated? What is the effect of activation?

A

TLR2/TLR4 -> causes upregulation of costimulation & pro-inflammatory cytokine production

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26
Q

What are the tolerogenic properties/effects of APCs of the liver? (4)

A
  1. Secretion of IL-10, TGF-β
  2. Non-productive activation of CD8+ T-cells
  3. Stimulation of FoxP3 Treg differentiation
  4. Expression of PD-L1
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27
Q

True or false: a healthy liver contains a lot of immune cells

A

False; healthy livers don’t contain a high amount of immune cells

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28
Q

What is the CD4/CD8 ratio in blood? What is the ratio in the liver?

A

Blood: CD4 > CD8
Liver: CD8 > CD4

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29
Q

The liver contains [more/less] NK and NK T-cells than blood

A

(Many) more

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30
Q

What is an important marker found on many intrahepatic lymphocytes? What does this marker tell us?

A

HLA-DR, indicating that these cells are of an activated phenotype (activation marker)

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31
Q

What percentage of cells in the liver are HLA-DR+? What is the percentage in blood?

A

Liver: 25-75%
Blood: <5%

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32
Q

Intrahepatic lymphocytes are [realtively low/normal/enriched] for activated memory cells

A

Enriched

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33
Q

How many % of intrahepatic T-cells express a γδ TCR? What is the function of these cells? Does blood contain many γδ TCR T-cells?

A

35% of intrahepatic T-cells express γδ TCR, indicating that they respond to lipid antigens expressed via CD1c
γδ T-cells are rare in blood

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34
Q

What is the effect of γδ T-cells on αβ T-cell responses?

A

Generally suppress αβ T-cell responses

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35
Q

What are NK T-cells? What do they recognize?

A

T-cells expressing semi-invariant TCRαβ -> recognize glycolipids & lipids

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36
Q

Where are T-cells normally located in the liver?

A

Sinusoids

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37
Q

Do hepatocytes perform antigen presentation?

A

In case of liver damage, the epithelial barrier between hepatocytes and T-cells in the sinusoids is broken. In these instances, hepatocytes can upregulate MHCI and express MHCII & costimulatory factors

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38
Q

Which cells are usually most important in immune-mediated liver diseases?

A

T-cells

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39
Q

True or false: T-cells usually reside in the liver

A

False; most T-cells only pass through the liver and don’t take up residence there

40
Q

HBV-specific T-cell response in chronic HBV-patients is [very strong, causing liver damage/weak, allowing the virus to thrive]

A

Response is weak, allowing the virus to persist

41
Q

What happens to the HBV-specific T-cell response when HBV is treated?

A

Number of T-cells starts to increase

42
Q

After how long is a viral hepatitis considered chronic?

A

> 6 months

43
Q

Where are lymphocytes located in case of chronic hepatitis? What can be said about the activity and type of these lymphocytes?

A

Around the portal tracts
Lymphocytes generally not very active
Type: inactive effector T-cells & Tregs

44
Q

Who are most of risk of establishing a chronic HBV infection?

A

Young children (around birth or <5 years), adults have a lower risk

45
Q

Which two treatments are available for HBV?

A
  1. PEG-IFNα (rarely used)
  2. Viral replication inhibitors
46
Q

What are the downsides of using PEG-IFNα for the treatment of HBV/HCV? (2)

A
  1. Severe side effects
  2. Not all patients respond (HBV ~30%, HCV 50-75%)
47
Q

Which two viral replication inhibitors are used for HBV?

A
  1. Entecavir
  2. Tenofovir
48
Q

What is the downside of viral replication inhibitor treatment for HBV/HCV?

A

Life-long treatment required

49
Q

What happens to HBV T-cell responses over time?

A

Gradually weaken -> few HBV-reactive T-cells found in blood of chronic patients

50
Q

How does the amount of HBV-specific T-cells correlate with HBV DNA load?

A

Inverse correlation -> the higher HBV DNA load, the lower the amount of HBV-specific T-cells

51
Q

What can be said about ALT levels in chronic HBV patients?

A

Relatively low ALT levels -> no acute liver damage

52
Q

How does chronic HBV cause loss of liver function?

A

Progressive loss of liver function and development of fibrosis/cirrhosis

53
Q

Against which viral antigens is the immune response aimed uring the acute stage of HBV infection? (3)

A
  1. HBcAg = core antigen
  2. HBV polymerase
  3. HBeAg = envelope
54
Q

What is the difference in antigen-specific T-cell responses in chronic hepatitis B compared to acute hepatitis B?

A

Chronic hepatitis: HbcAg & HBV polymerase -> no HBeAg

55
Q

What are the stages of HBV-infection? (4)

A
  1. Immunotolerant (IT)
  2. Immunoactive (IA)
  3. Inactive carrier (IC)
  4. HBeAg-negative (ENEG)
56
Q

Which cells are active during the immunoactive stage of HBV-infection? (3) Which group of genes do they express?

A

B (++), T (+), NK (+)

Interferon-stimulated genes

57
Q

Which cells are active during the inactive carrier stage of HBV-infection?

A

B, T

58
Q

What do peaks of ALT during chronic HBV-infection indicate?

A

High liver damage due do virus flare-ups

59
Q

HBV DNA is [high/low] during the inactive carrier stage of HBV-infection

A

Low

60
Q

Which cells are active during the HBe-Ag-negative stage of HBV-infection?

A

B, T, NK

61
Q

Which host mechanisms contribute to HBV chronicitity? (5)

A
  1. Tregs
  2. Immunosuppressive cytokines (IL-10, TGF-β)
  3. Impaired NK-cell function
  4. Myeloid suppressor cells
  5. T-cell exhaustion
62
Q

How does T-cell exhaustion contribute to HBV chronicity?

A

Overstimulation of T-cells in chronic infections causes them to gradually lose their function

63
Q

What is a marker of T-cell exhaustion?

A

PD-1
Found in high levels on HBV-specific T-cells in chronic infection

64
Q

What happens when an exhausted T-cell gets stimulated by antigen on an APC?

A

Limited response or apoptosis

65
Q

How can T-cell exhaustion be overturned in chronic HBV infection? (4)

A
  1. Reducing antigen load
  2. Blockade of inhibitory receptors
  3. Blockage of other inhibitory pathways
  4. Immunotherapeutic boosting of T-cells
66
Q

How can antigen load be reduced in chronic hepatitis B (with the aim of reducing T-cell exhaustion) (3)

A
  1. Promoting viral clearance
  2. Inhibiting secretion of viral antigens
  3. Decreasing production of viral antigens
67
Q

How can the production of viral antigens be decreased in chronic HBV? What is the effect on T-cells?

A

Viral replication inhibitors -> less antigens = less T-cell stimulation -> T-cell exhaustion lessens

68
Q

Which inhibitory receptors can be blocked to overcome T-cell exhaustion (4)

A
  1. PD-1
  2. CTLA-4
  3. LAG3
  4. Trim3
69
Q

Which inhibitory pathways can be targeted to overcome T-cell exhaustion? (3)

A
  1. Inhibitory cytokines
  2. Inhibitory NK-cells
  3. Tregs
70
Q

How can T-cells be immunogenically boosted to overcome exhaustion? (3)

A
  1. Vaccines
  2. TLR agonists
  3. Cytokines
71
Q

How many % of HCV cases become chronic?

A

60-80% (adults)

72
Q

Which two treatments are available for HCV?

A
  1. PEG-IFNα + ribavirin
  2. Viral replication inhibitors
73
Q

Which viral replication inhibitor cocktail is available for HCV?

A

Sofosbuvir + simeprevir

74
Q

How many % of chronic HCV patients develop cirrhosis?

A

20%

75
Q

What is the first sign of HCV infection (serological)?

A

Rapid increase of HCV DNA

76
Q

How long does it take for an immune response against HCV to kick in? How can this be detected?

A

At least 7 weeks -> increase of ALT, showing liver damage by inflammation

77
Q

Which viral mechanisms inhibit HCV clearing in the initial phase? (2)

A
  1. Endogenous IFNα is insufficient & inhibited by HCV
  2. NK-cell killing of infected cells is inhibited by HCV
78
Q

What is the Th-subset that is most active in HCV?

A

Th1

79
Q

T-cell responses against HCV are directed against [one viral epitope/multiple viral epitopes]

A

Multiple viral epitopes

80
Q

Which two architectural patterns can be used to describe the liver?

A
  1. Venocentric hepatic angioarchitecture -> lobular structure
  2. Acinar structure
81
Q

What is the lobular architectural pattern of the liver made up of?

A

It is centered around the central vein, with 3-6 portal triads in the corners, forming a hexagon

82
Q

Which three structures can be found in the portal tract? How can they be distinguished?

A
  1. Portal vein = largest
  2. Hepatic artery = made up out of endothelium
  3. Bile duct = made up out of cuboid epithelium
83
Q

What is the acinar architectural pattern of the liver based on?

A

The amount of oxygen found in the liver tissue -> determined by their distance from the a. hepatica

84
Q

Which three zones can be distinghuished in the acinar architectural pattern of the liver? What are their characteristics?

A

Zone 1 = directly surrounding the a. hepatica -> most oxygen
Zone 2 = intermediary zone
Zone 3 = around the central vein -> least oxygen

85
Q

Which of the zones in the acinar architectural of the liver will get damaged first in case of ischaemia?

A

Zone 3 -> contains least oxygen

86
Q

What surrounds the structure of the portal triad?

A

Fibrous tissue with (some) lymphocytes and mast cells

87
Q

How are hepatocytes arranged in liver tissue?

A

Trabecular structures of one cell layer thick

88
Q

What do hepatocytes look like?

A

Eosinophilic granular & glycogen-rich cytoplasm. Can be polynuclear.

89
Q

In what pattern can inflammatory cells be seen in (acute) liver inflammation?

A

Sticking together in patches -> causes spotty necrosis

90
Q

What happens when patches of spotty necrosis become bigger?

A

Bridging necrosis between the central vein and the portal tract

91
Q

What will happen to ALAT/ASAT in serum in case of bridging necrosis?

A

Strong increase due to high hepatocyte necrosis

92
Q

What are the histological features of acute hepatitis? (6)

A
  1. Predominantly lobular inflammation, not in portal areas
  2. Regeneration and disarray of hepatocytes
  3. Apoptotic bodies
  4. Ballooning & proliferation of hepatocytes
  5. Hepatocyte dropout/necrosis
  6. Cholestasis
93
Q

What are the common features of chronic hepatitis? (5)

A
  1. Chronic inflammatory cell infiltration in the portal tracts
  2. Interface hepatitis -> inflammatory activity at the portal/lobular interface (lymphocytes/plasma cells destroying hepatocytes around the portal tract)
  3. Intralobular necroinflammatory activity (but not as pronounced as in acute hepatitis)
  4. Briding necrosis
  5. Fibrosis
94
Q

What are additional histological features that can be found in chronic hepatitis B? (2) (in addition to ‘common’ chronic features) Are these specific for HBV?

A
  1. Ground-glass hepatocytes -> abundant, finely granular & light eosinophilic cytoplasm, with a clear halo around the peripheral portion of the cell
  2. Sanded nuclei -> pale, eosinophilic & finely granular

These are pathognomonic for HBV

95
Q

What are additional histological features that can be found in chronic hepatitis C? (4) (in addition to ‘common’ chronic features) Are these specific for HCV?

A
  1. Steatosis
  2. Dense lymphoid aggregates in portal tracts
  3. Bile duct damage
  4. Mild hemosiderin deposits

These are not specific for HCV, but could point to HCV

96
Q

Is HCV a likely cause of inflammation if steatosis is high?

A

No; in this case, other causes should be investigated

I&I WC1 (20 decks)

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