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BSMS302 > 7. Pathogenesis of viral hepatitis > Flashcards

7. Pathogenesis of viral hepatitis Flashcards

1
Q

Stages of viral hepatitis

A

Subclinical
Acute hepatitis
Acute liver failure
Chronic

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2
Q

chronic hepatitis

A

abnormal LFTs and positive serological markers >6 months

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3
Q

Histological staging of hepatic fibrosis

A

No fibrosis
Stage 1: fibrous expansion of some portal areas
Stage 3: fibrous expansion of most portal areas with occasional portal to portal bridging
Stage4: fibrous expansion of portal areas witith marked bridging (portal to portal and portal to central)
stage 5,6: cirrhosis, probable or defined

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4
Q

Hep B virus clinical epidemiology

A

Alaska and northern Canada
Parts of South America
Most of Africa
Asia

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5
Q

Risk factors for HBV

A 
Ethnicity (Asian, pacific asian, native americans and Alaskans, Hispanics)
IDU
MSM
HIV
HCW (healthcare workers)
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6
Q

Hep B virus genome

A 
Lipid bilayers
DNA polymerase
RT/pol
HbcAg
4 ORF
Pre S
precore-core
polymerase
X
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7
Q

HBV replication

A

DNA genome which makes an RNA intermediate which is replicated by reverse transcription

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8
Q

HBV lifecycle

A

HBV core particle enters cell
enters nucleus, replicates, leaves nucleus and is translated to make the virus which buds into the ER and is then transported to cell membrane via vesicle

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9
Q

How does immune system deal with viruses

A

TLR3 recognises PAMP and activates IFN regulatory genes through RIGI signalling.

IFN reg genes activate IFN stimulatory genes which cause production of IFN alpha and beta.

IFNs cause:

  • activation of NK, CD8, DCs
  • down regulation of viral proteins
  • inhibition of viral gene expression
  • perforin secretion to kill cells
  • promotes MHC class I expression on APCs which leads to adaptive immunity response
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10
Q

How does HBV evade immune detection?

A

innate system cccDNA
not recognised by host immune system?
interferes with TLR expression?

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11
Q

The role of HBsAb

A

Provide life long immunity

form complex with neutralising antibody and prevents uptake by uninfected hepatocytes

neutralising Abs dont contribute to any early viral clearance

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12
Q

Early and late immune responses against HBV

A

Early: CD8 releases IFN gamma and IFN alph which are non-cytopathic to the Hep-B infected cell

Late: Cytopathic response. CD8 Fas ligand/perforin causes apoptosis of the infected cell

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13
Q

Resolved infection

A

95% immunocompetent adults
life-long immunity
due to

Early CD4+ priming which contributes to a synchronised influx of HBV-specific CD8 cells which result in viral clearance

Polyclonal and multispecific intrahepatic CD8+ cells response

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14
Q

Persistant infection factors

A

Age at infection

  • HbeAg crosses placenta and induces tolerance to HbcAg (the most immunogenic)
  • which suppresses immune mediated elimination of infected cells and switches the immune response to TH2 (Th2 response is anti-inflammatory)

Immunosuppression/ inadequate cell-mediated immunity - weak/narrow intrahepatic CD4+/CD8+ cell response

  • high viral load: anergy, exhaustion of T and B cells
  • antiviral therapy: recovery of HBV spefic CD4+/CD8+ cells
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15
Q

What is the only antigen that crosses the placenta?

A

HbeAg

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16
Q

HBV X protein

A

HBV X protein interferes with antigen processing and presentation and protects cccDNA

leads to persistant infection

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17
Q

Persistant infection immune system

A

Foxp3 on T regs suppresses HBV specific T cells

CD28, which promotes apoptosis, is upregulated, thereby downregulating virus specific T cells

CTLA4, binds Cd80 or CD86 on the surface of APCs and switches off the APCs

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18
Q

IL10 in persistent infection

A

IL10 inhibits IFN-g and IFN-a and sosuppresses CD4+ and CD8+ and downregulates antiviral immune responses.

IL10 also
promotes apoptosis of plasmacytoid dendritic cells

IL10 attenuates inflam responses at cost of efficient antiviral immune responses

blocking IL-10 receptors in animal models restores immune response resulting in viral clearance

19
Q

TH2 involvement in Hep B infection

A

Can lead to persistent infection due to release of IL10 and IL4 which are anti-inflammatory and promote down regulation of the antiviral response

20
Q

Acute HBV infection serology

A

HBeAg exposure first for around 16 weeks, Ab start being made around 6 weeks after exposure
IgM anti-HBc/HbcAb up to 32 weeks after exposure
then from 32 onwards anti HBs/HbsAb

21
Q

Chronic Hep B virus infection serology

A

HBeAg around chronically
Only IgM anti-Hbc made, no anti-Hbs afterwards, so HbsAg stays high even years after exposure

HBV DNA correlates with risk of cirrhosis and HCC

22
Q

Natural progression of HBV infection

A
  1. perinatal transmission
  2. immune tolerant phase
  3. Active phase (HbeAg+ immune) (or horizontal transmission can lead straight to active phase)
  4. AntiHbe seroconversion (90%)
  5. inactive HBV (90%) which goes to anti-Hbe+ immune active phase(20-40%)
  6. Clearance of HbsAg in 0.5-1% of infected
    sometimes there is reverse seroconversion where it goes back to an active phase w HbeAg+
23
Q

HBV natural history

A

> 90% of acute infection progresses to chronic in children, <5% in adults because they can clear it with their own immune response

5% of chronic infection leads to HCC (liver cancer)

24
Q

Infection presentation in children vs adults

A

In adults, acute infection is generally accompanied by symptoms (jaundice, fatigue, myaglia)

in children, symptoms are usually sub-clinical.

Most adults will clear the virus through their own immune response, preventing progression to chronic hepatitis B. In contrast, almost all infected children will progress to chronic hepatitis B.

Individuals with chronic hepatitis B are at a significantly increased risk for developing hepatocellular carcinoma (HCC), cirrhosis, or liver failure from ongoing liver injury (especially if have precore and core promoter mutation). Cirrhosis can lead to HCC

HCC or liver failure lead to liver transplantation or death

25
Q

Chronic HBV treatment

A

Pegylated interferon
Tenofovir/tenofovir alafenamide
Enetacir

26
Q

How do you define HBV cure?

A

Cure defined by loss of HBsAg but this happens only rarely

27
Q

Course of Hep B infection determinants

A 
Age at infection
immunosuppression
Host immune response
HBV genotype and mutations
Coexisting risk factor e.g. alcohol, HCV, HIV
28
Q

HBV mutations

A

Pre-S1/PreS2/S promoter leads to missassembly and fibrosing cholestatic hepatitis

S mutation leads to vaccine and immune escape through alteration of B and T cell epitopes

Pol mutations lead to viral latency and persistance

Core promoter leads to severe hepatitis, HCC and ALF

29
Q

HBV in general

A

HBV evades innate immune responses ?through cccDNA

Early priming of CD4 cells -> CD8 cell activation

Humoral response late and doesn’t contribute to viral clearance but reduces viral spread.

95% of immunocompetent adults clear the infection

90% of neonates develop chronic infection

30
Q

Hep C virus

A

RNA virus
rapid rate of replication
80% develop chronic infection
No vaccine

31
Q

HCV pathogenesis

A

HCV gets into peripheral bood and then infects hepatocytes. HCV replicates in hepatocytes then HCV peptides are displayed on MHC class I to CD8+ T cells which release IFN-g

Dendritic cells (or other APCs) also takes up HCV antigens and presents them on MHC class I to CD8 and on MHC II to CD4+ cells.

Th2 CD4+ cells get educated and release HCV-antibodies in the peripheral blood

32
Q

Differences in T cell types in HCV pathogenesis

A

More CD8+ T cells in resolved HCV than in chronic, showing that CD8+ T cells are needed for viral clearance

33
Q

Resolving HCV infection

A

high viraemia in early phase, then T cell responses initiated and neutralising antibodies. The T ell response conittnues in the late phase

34
Q

Chronic HCV infection

A

High viraemia in early phase which dips but stays high in late phase
small T cell responses in early phase
Neutralising antibodies made in small amounts until late phase where neutralising antibodies increase

35
Q

What leads to HCV chronicity?

A

High replication rate and viral antigen load so get CD8/CD4 anergy/exhaustion

High error rate of RdRpol leads to mutations and quasispecieis escape immune response

HCV proteins interfere w immune responses

Neutralising Sbs develop too slowly n too late and are short lived so there are HCV escape mutants

36
Q

HCV proteins which interfere w immune responses

A

NS proteins inhibit innate immune response by disrupting RIG-I signalling and therefore stop TLR recognition

Core protein downregulates IL12 production

37
Q

Spectrum of HCV disease

A

Acute infection can sometimes recover in 15-45% of cases, especially if female, jaundiced, low VL, GT3, white

55-85% of acute infection lead to chronic HCV infection which canlead to cirrhosis, HCC, endstage liver disease which leads to liver transplant or death

38
Q

Risk factors for liver cirrhosis

A 
Age
Male
Alcohol
HIV
HBV
39
Q

Acute HCV infection serology w recover vs recovery

A

HCV Abs in acute

HCV Abs but HCV RNA in chronic

40
Q

HCV inhibitors

A

NS3/4A protease inhibitors

NS5A inhibitors

NS5B polymerase inhibitors

41
Q

HCV drugs

A 
Ledipasvir 
Ombitasvi
Daclatasvir
Elbasvir
Velpatasvir
Pibrentasvir
Grazoprevir
Paritaprevir
Simeprevir
Glecaprevir
42
Q

Fibrosing cholestatic hepatitis

A
  1. Overimmunosuppresion (corticosteroids)
  2. Increased HCV entry so increased cell-to-cell spread
  3. Failure of HCV specific T cell response
  4. Predominantly TH2 intrahepatic cytokine response
  5. Increased HCV replication
  6. Stable viral quasispecies
  7. High level ISG induction
  8. Activation of cell death pathway
  9. Induction o IL8 and resistance to IFN
  10. Oxidative stress
  11. Hepatic inflammation, hepatocyte ballooning, severe cholestasis
43
Q

HCV in general

A

Not directly cytopathic
up to 80% can develop chronic disease
defects in both humoral and especially cellular immunity
neutralising antibody does not prevent reinfection
high replicative rate and generation of escape mutants
Direct acting antivirals resulted in paradigm shift in HCV management with >95% SVR rates

BSMS302 (10 decks)

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