Hepatology Flashcards
How many segments and lobules does the liver contain?
8 segments, ~100 lobules
What is the function of sinusoids in the liver?
Slow blood flow, allowing hepatocytes to get in contact with blood
True or false: hepatocytes directly contact bloods in the sinusoids
False; they are seperated by endothelial cells and sinusoidal cells
What is the space of Disse? Which cell types can be found here? (2)
Perisinusoidal space -> contains hepatic stellate cells & Kupffer cells
What are the metabolic functions of the liver? (7)
- Storage of nutrients
- Gluconeogenesis
- Deamination of amino acids
- Production of non-essential amino acids
- Fatty acid oxidation
- Production of cholesterol & lipoproteins
- Production of phospholipids
How is cholesterol excreted by the liver?
As bile salts
Which important groups of factors are synthesized by the liver? (5)
- Albumin
- Coagulation factors
- CRP
- Complement proteins
- Soluble PRRs
What is CRP? When is it released?
Pentraxin family member, released when IL-6 is produced. Binds lipids on bacterial surfaces and activates the classical complement pathway, causing bacteriolysis
What is LBP? What is its function?
Acute phase protein that binds LPS in circulation and transfers it to CD14 -> supports binding of LPS to TLR4
What is the function of soluble CD14, secreted by the liver?
Supports binding of LPS to TLR4 in case of absence of membrane-bound CD14
What should the liver be tolerogenic towards?
Food proteins & (endo)toxins
In which situations does unwanted hepatic tolerance occur? (3)
- HBV/HCV
- Plasmodium sporozoite
- Tumour metastases
What does the liver have immunity against?
- HAV
- HBV (early stages)
- Many bacterial species
What is the unique property of the liver when it comes to LTx?
HLA matching is not required due to its tolerogenic nature
LTx also confers protection against rejection of other solid organs from the same donor
Which immune cells can be found in the liver? (7)
- Kupffer cells -> antigen-presenting cells
- DCs
- Liver sinusoidal endothelial cells (LSEC)
- NK-cells
- NK T-cells
- Regular T- and B-cells
- Hepatic stellate cells
What is the function of hepatic stellate cells?
Vitamin A storage
What is the function of LSECs?
To remove waste products from blood and to capture pathogens, proteins and toxins from blood
How do LSECs capture antigens?
Scavenger receptors and carbohydrate receptors
LSECs can act as APCs. Which type of MHC do they use? Are they mainly tolerogenic or immunogenic?
Both MHCI/MHCII, mainly tolerogenic through low-level activation and secretion of anti-inflammatory cytokines
What is the function of Kupffer cells?
Tissue-resident macrophages -> phagocytose and degrade particulate materials from blood
Why do Kupffer cells express FcR?
Allows for clearaence of immune complexes
Why do Kupffer cells express complement receptors?
Clearance of C3b-coated bacteria
Why do Kupffer cells express TLR4?
Clearance of LPS from portal blood
Kupffer cells are mainly [tolerogenic/immunogenic] APCs?
Tolerogenic -> intermediate MHCII/costimulation & suppression of T-cell activation, induction of Tregs
How are Kupffer cells activated? What is the effect of activation?
TLR2/TLR4 -> causes upregulation of costimulation & pro-inflammatory cytokine production
What are the tolerogenic properties/effects of APCs of the liver? (4)
- Secretion of IL-10, TGF-β
- Non-productive activation of CD8+ T-cells
- Stimulation of FoxP3 Treg differentiation
- Expression of PD-L1
True or false: a healthy liver contains a lot of immune cells
False; healthy livers don’t contain a high amount of immune cells
What is the CD4/CD8 ratio in blood? What is the ratio in the liver?
Blood: CD4 > CD8
Liver: CD8 > CD4
The liver contains [more/less] NK and NK T-cells than blood
(Many) more
What is an important marker found on many intrahepatic lymphocytes? What does this marker tell us?
HLA-DR, indicating that these cells are of an activated phenotype (activation marker)
What percentage of cells in the liver are HLA-DR+? What is the percentage in blood?
Liver: 25-75%
Blood: <5%
Intrahepatic lymphocytes are [realtively low/normal/enriched] for activated memory cells
Enriched
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?
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
What is the effect of γδ T-cells on αβ T-cell responses?
Generally suppress αβ T-cell responses
What are NK T-cells? What do they recognize?
T-cells expressing semi-invariant TCRαβ -> recognize glycolipids & lipids
Where are T-cells normally located in the liver?
Sinusoids
Do hepatocytes perform antigen presentation?
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
Which cells are usually most important in immune-mediated liver diseases?
T-cells
True or false: T-cells usually reside in the liver
False; most T-cells only pass through the liver and don’t take up residence there
HBV-specific T-cell response in chronic HBV-patients is [very strong, causing liver damage/weak, allowing the virus to thrive]
Response is weak, allowing the virus to persist
What happens to the HBV-specific T-cell response when HBV is treated?
Number of T-cells starts to increase
After how long is a viral hepatitis considered chronic?
> 6 months
Where are lymphocytes located in case of chronic hepatitis? What can be said about the activity and type of these lymphocytes?
Around the portal tracts
Lymphocytes generally not very active
Type: inactive effector T-cells & Tregs
Who are most of risk of establishing a chronic HBV infection?
Young children (around birth or <5 years), adults have a lower risk
Which two treatments are available for HBV?
- PEG-IFNα (rarely used)
- Viral replication inhibitors
What are the downsides of using PEG-IFNα for the treatment of HBV/HCV? (2)
- Severe side effects
- Not all patients respond (HBV ~30%, HCV 50-75%)
Which two viral replication inhibitors are used for HBV?
- Entecavir
- Tenofovir
What is the downside of viral replication inhibitor treatment for HBV/HCV?
Life-long treatment required
What happens to HBV T-cell responses over time?
Gradually weaken -> few HBV-reactive T-cells found in blood of chronic patients
How does the amount of HBV-specific T-cells correlate with HBV DNA load?
Inverse correlation -> the higher HBV DNA load, the lower the amount of HBV-specific T-cells
What can be said about ALT levels in chronic HBV patients?
Relatively low ALT levels -> no acute liver damage
How does chronic HBV cause loss of liver function?
Progressive loss of liver function and development of fibrosis/cirrhosis
Against which viral antigens is the immune response aimed uring the acute stage of HBV infection? (3)
- HBcAg = core antigen
- HBV polymerase
- HBeAg = envelope
What is the difference in antigen-specific T-cell responses in chronic hepatitis B compared to acute hepatitis B?
Chronic hepatitis: HbcAg & HBV polymerase -> no HBeAg
What are the stages of HBV-infection? (4)
- Immunotolerant (IT)
- Immunoactive (IA)
- Inactive carrier (IC)
- HBeAg-negative (ENEG)
Which cells are active during the immunoactive stage of HBV-infection? (3) Which group of genes do they express?
B (++), T (+), NK (+)
Interferon-stimulated genes
Which cells are active during the inactive carrier stage of HBV-infection?
B, T
What do peaks of ALT during chronic HBV-infection indicate?
High liver damage due do virus flare-ups
HBV DNA is [high/low] during the inactive carrier stage of HBV-infection
Low
Which cells are active during the HBe-Ag-negative stage of HBV-infection?
B, T, NK
Which host mechanisms contribute to HBV chronicitity? (5)
- Tregs
- Immunosuppressive cytokines (IL-10, TGF-β)
- Impaired NK-cell function
- Myeloid suppressor cells
- T-cell exhaustion
How does T-cell exhaustion contribute to HBV chronicity?
Overstimulation of T-cells in chronic infections causes them to gradually lose their function
What is a marker of T-cell exhaustion?
PD-1
Found in high levels on HBV-specific T-cells in chronic infection
What happens when an exhausted T-cell gets stimulated by antigen on an APC?
Limited response or apoptosis
How can T-cell exhaustion be overturned in chronic HBV infection? (4)
- Reducing antigen load
- Blockade of inhibitory receptors
- Blockage of other inhibitory pathways
- Immunotherapeutic boosting of T-cells
How can antigen load be reduced in chronic hepatitis B (with the aim of reducing T-cell exhaustion) (3)
- Promoting viral clearance
- Inhibiting secretion of viral antigens
- Decreasing production of viral antigens
How can the production of viral antigens be decreased in chronic HBV? What is the effect on T-cells?
Viral replication inhibitors -> less antigens = less T-cell stimulation -> T-cell exhaustion lessens
Which inhibitory receptors can be blocked to overcome T-cell exhaustion (4)
- PD-1
- CTLA-4
- LAG3
- Trim3
Which inhibitory pathways can be targeted to overcome T-cell exhaustion? (3)
- Inhibitory cytokines
- Inhibitory NK-cells
- Tregs
How can T-cells be immunogenically boosted to overcome exhaustion? (3)
- Vaccines
- TLR agonists
- Cytokines
How many % of HCV cases become chronic?
60-80% (adults)
Which two treatments are available for HCV?
- PEG-IFNα + ribavirin
- Viral replication inhibitors
Which viral replication inhibitor cocktail is available for HCV?
Sofosbuvir + simeprevir
How many % of chronic HCV patients develop cirrhosis?
20%
What is the first sign of HCV infection (serological)?
Rapid increase of HCV DNA
How long does it take for an immune response against HCV to kick in? How can this be detected?
At least 7 weeks -> increase of ALT, showing liver damage by inflammation
Which viral mechanisms inhibit HCV clearing in the initial phase? (2)
- Endogenous IFNα is insufficient & inhibited by HCV
- NK-cell killing of infected cells is inhibited by HCV
What is the Th-subset that is most active in HCV?
Th1
T-cell responses against HCV are directed against [one viral epitope/multiple viral epitopes]
Multiple viral epitopes
Which two architectural patterns can be used to describe the liver?
- Venocentric hepatic angioarchitecture -> lobular structure
- Acinar structure
What is the lobular architectural pattern of the liver made up of?
It is centered around the central vein, with 3-6 portal triads in the corners, forming a hexagon
Which three structures can be found in the portal tract? How can they be distinguished?
- Portal vein = largest
- Hepatic artery = made up out of endothelium
- Bile duct = made up out of cuboid epithelium
What is the acinar architectural pattern of the liver based on?
The amount of oxygen found in the liver tissue -> determined by their distance from the a. hepatica
Which three zones can be distinghuished in the acinar architectural pattern of the liver? What are their characteristics?
Zone 1 = directly surrounding the a. hepatica -> most oxygen
Zone 2 = intermediary zone
Zone 3 = around the central vein -> least oxygen
Which of the zones in the acinar architectural of the liver will get damaged first in case of ischaemia?
Zone 3 -> contains least oxygen
What surrounds the structure of the portal triad?
Fibrous tissue with (some) lymphocytes and mast cells
How are hepatocytes arranged in liver tissue?
Trabecular structures of one cell layer thick
What do hepatocytes look like?
Eosinophilic granular & glycogen-rich cytoplasm. Can be polynuclear.
In what pattern can inflammatory cells be seen in (acute) liver inflammation?
Sticking together in patches -> causes spotty necrosis
What happens when patches of spotty necrosis become bigger?
Bridging necrosis between the central vein and the portal tract
What will happen to ALAT/ASAT in serum in case of bridging necrosis?
Strong increase due to high hepatocyte necrosis
What are the histological features of acute hepatitis? (6)
- Predominantly lobular inflammation, not in portal areas
- Regeneration and disarray of hepatocytes
- Apoptotic bodies
- Ballooning & proliferation of hepatocytes
- Hepatocyte dropout/necrosis
- Cholestasis
What are the common features of chronic hepatitis? (5)
- Chronic inflammatory cell infiltration in the portal tracts
- Interface hepatitis -> inflammatory activity at the portal/lobular interface (lymphocytes/plasma cells destroying hepatocytes around the portal tract)
- Intralobular necroinflammatory activity (but not as pronounced as in acute hepatitis)
- Briding necrosis
- Fibrosis
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?
- Ground-glass hepatocytes -> abundant, finely granular & light eosinophilic cytoplasm, with a clear halo around the peripheral portion of the cell
- Sanded nuclei -> pale, eosinophilic & finely granular
These are pathognomonic for HBV
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?
- Steatosis
- Dense lymphoid aggregates in portal tracts
- Bile duct damage
- Mild hemosiderin deposits
These are not specific for HCV, but could point to HCV
Is HCV a likely cause of inflammation if steatosis is high?
No; in this case, other causes should be investigated
