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302/308 > Pathogenesis of viral hepatitis > Flashcards

Pathogenesis of viral hepatitis Flashcards

1
Q

Viral hepatitis

A
  • Subclinical
  • Acute hepatitis: more florid the attack, chronic sequelae less likely
  • Acute liver failure
  • Chronic: abnormal LFTs and positive serological markers > 6 months
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2
Q

Histological staging of hepatic fibrosis

A

Stage 1 - Fibrous expansion of some portal areas
Stage 3 - Fibrous expansion of most portal areas with occasional portal to portal bridging
Stage 4 - Fibrous expansion of portal areas with marked bridging(portal to portal and portal to central)
Stage 5,6: Cirrhosis, probable or defined
Cirrhotic liver - Gross anatomy of cadaver

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3
Q

HBV - replication

A
  • Replication of DNA genome by reverse transcription of RNA intermediate
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4
Q

HBV - recognition

A

PAMP recognised by TLR3 –RIG-1–> Interferon regulatory factors –NF-kB–> Interferon stimulating genes –INF alpha/beta–>

  • Down regulates viral protein synthesis
  • inhibit viral replication
  • promote adaptive immunity via MHC class I expression on APC,
  • activates NK, CD8 and dendritic cells
  • activate cell death through secretions of perforins
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5
Q

HBsAb

A
  • Development of HBsAb provides life long immunity

- Neutralising antibody - forms complex with HBSAg and prevents uptake by uninfected hepatocytes

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6
Q

What is the fas ligand

A
  • Fas ligand is a type II transmembrane protein that belongs to the tumour necrosis factor
  • Its binding with its receptor induces apoptosis
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7
Q

Resolved infection

A
  • 95% immunocompetent adults
  • Life long immunity
  • Polyclonal and multispecific intrahepatic CD8+ cells response
  • Early CD4+ priming contribute to synchronised influx HBV specific CD8+ cells resulting in viral clearance
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8
Q

Persistent infection

A

Age at infection:
HbeAg only antigen that crosses the placenta
- Induces tolerance to HbcAg (most immunogenic)
- Suppress immune mediated elimination of infected cells
- Switches immune response to Th2

Immunosuppression - inadequate CMI
Weak/narrow intrahepatic CD4+/

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9
Q

Effect of HBV X protein on antigen processing

A
  • HBV X protein interferes with antigen processing and presentation - protects ccc DNA
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10
Q

Effect of Foxp3

A

Foxp3 (forkheadP3 transcription factor) expressed on Tregs - suppress HBV specific T cell responses

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11
Q

Programmed death-1 receptor

A

Programmed death-1 receptor (CD28) up regulated - promote apoptosis thereby down regulate virus specific T cell responses - exhausted CD8 cells upregulate PD-1 present on T, B, NK, kupffer cells, Treg.Pd1 stimulated by interferon gamma and PD-2 by IL-4

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12
Q

Cytotoxic T-lymphocyte antigen 4(CTLA4)(CD152)

A
  • “Immune off” switch when bound to CD 80 or CD86 on the surface of antigen-presenting cells
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13
Q

Persistent infection: IL-10

A

Down regulates antiviral immune responses

  • CD4+ and CD8+ suppression with inhibition of IFN-gamma and IFN-alpha production
  • Promotes apoptosis of plasmacytoid dendritic cells
  • Attenuates inflammatory responses but at cost of efficient antiviral immune responses
  • Animal models - therapeutic blockade of IL-10 receptor with specific antibody restores immune response resulting in viral clearance
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14
Q

Acute hep b virus infection with recovery typical serologic course

A

check powerpoint for graph - slide 16

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15
Q

Progression to chronic hep B virus infection - typical serologic course

A

check powerpoint for graph - slide 16

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16
Q

What does HBV DNA correlate with

A

HBV DNA correlates with risk of cirrhosis and HCC

17
Q

Natural progression of HBV infection

A

Perinatal transmission -> immune tolerant phase -> treatment -> anti-HBc seroconversion –> 80-20% inactive HBV + 10-20% anti-HBc + immune active phase

Inactive HBV -> clearance of HBsAg

18
Q

What can acute infection - HBV progress to

A

> 90% of infected children progress to chronic disease

<5% of infected adults progress to chronic disease

19
Q

What can chronic infection progress to

A
  • 5-10% of chronic HBV-infected individuals –> liver cancer(HCC)
  • ongoing liver injury
  • Pre-core and core promoter mutation –30% of chronic HBV infected individuals–> cirrhosis
20
Q

What can ongoing liver injury lead to

A
  • 5 yr probability (8-20%) –> cirrhosis –> 25% decompensate in 5 yrs, 5yr survival 14-35% –> liver failure or liver cancer
21
Q

What is chronic hepatitis B acute infection in adults generally accompanied by

A
  • Jaundice, fatigue, myalgia - while in children, symptoms are usually sub-clinical
  • The majority of adults will clear the virus through their own immune response, preventing progression to chronic hepatitis B. In contrast, all infected children will progress to chronic hepatitis B
22
Q

What are individuals with chronic hepatitis B at risk of developing

A
  • Significant risk for developing hepatocellular carcinoma(HCC), cirrhosis, or liver failure
  • HCC or liver failure lead to liver transplantation or death
23
Q

Chronic HBV treatment

A
  • Pegylated interferon
  • Tenofovir/tenofovir alafenamide
  • Entecavir
  • Cure defined by loss of HBsAg - happens only rarely
24
Q

Course of hepatitis B infection

A
  • Age at infection
  • Immunosuppression
  • Host immune response
  • HBV genotype and mutations -
  • Coexisting risk factor - alcohol, HCV, HIV
25
Q

HBV - humoral response

A
  • Humoral response late - no contribution to viral clearance but reduce viral spread
  • HBsAb prevents reinfection
  • 95% of immunocompetent adults clear the infection
  • 90% neonates develop chronic infection
26
Q

Hep C virus

A
  • RNA virus
  • Rapid rate of replication
  • 80% develop chronic infection
  • No vaccine
27
Q

Hep C pathogenesis

A

HCV is a non-cytopathic virus that enters the liver cell and undergoes replication simultaneously causing cell necrosis by several mechanisms including immune-mediated cytolysis in addition to various other phenomena such as hepatic steatosis, oxidative stress and insulin resistance

28
Q

HCV - why chronicity

A

High replicative rate and viral antigen load

  • CD8+/CD4+ anergic/exhausted: unable to proliferate/secrete cytokines
  • Display normal immune responses to other viruses

High error rate of RNA dependent RNA polymerase leading to mutations (quasispecies)
- Escape neutralising antibodies and cellular immune responses

29
Q

HCV interference with immune response

A

HCV proteins interfere with immune response

  • NS proteins inhibit innate immune responses(recognition of TLR) through disruption of RIG-I signalling
  • Core protein down regulates IL-12 production
Neutralising AB (core, envelope, NS3, NS4) 
- Develop too slowly, too late, short lived inducing HCV escape mutations
30
Q

IL28B

A
  • IL28B is involved in immune response to HCV
  • 3 subtypes - CC, CT, TT
  • People with CC have strongest immune response to HCV
31
Q

Will chronic HCV always cause cirrhosis

A
  • Only moderate and severe

- Dependent on age, gender(male more likely), alcohol, HIV, HBV

32
Q

Examples of antivirals used in curative treatment of HCV

A
  • NS3/4A protease inhibitors
  • NS5A inhibitors
  • NS5B polymerase inhibitors
33
Q

Examples of NS3/4A protease inhibitors

A
  • Grazoprevir

- Paritaprevir

34
Q

Examples of NS5A inhibitors inhibitors

A
  • Ledipasvir (1, 4-6)

- Ombitasvir (1)

35
Q

NS5B RNA polymerase inhibitors

A
  • Sofosbuvir (1-4)

- Dasabuvir(1)

36
Q

Genotype 1

A

Two of the strongest SVR predictors are virus-related: the amount of HCV in the bloodstream (called
viral load) and the strain of HCV (called genotype). For example, HCV genotype 1 is harder to cure with PEG-IFN and RBV than genotypes 2 and 3

302/308 (22 decks)

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