Pathogenesis of viral hepatitis

Question 1

Viral hepatitis

Answer 1

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

Question 2

Histological staging of hepatic fibrosis

Answer 2

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

Question 3

HBV - replication

Answer 3

• Replication of DNA genome by reverse transcription of RNA intermediate

Question 4

HBV - recognition

Answer 4

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

Question 5

HBsAb

Answer 5

• Development of HBsAb provides life long immunity

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

Question 6

What is the fas ligand

Answer 6

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

Question 7

Resolved infection

Answer 7

• 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

Question 8

Persistent infection

Answer 8

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+/

Question 9

Effect of HBV X protein on antigen processing

Answer 9

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

Question 10

Effect of Foxp3

Answer 10

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

Question 11

Programmed death-1 receptor

Answer 11

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

Question 12

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

Answer 12

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

Question 13

Persistent infection: IL-10

Answer 13

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

Question 14

Acute hep b virus infection with recovery typical serologic course

Answer 14

check powerpoint for graph - slide 16

Question 15

Progression to chronic hep B virus infection - typical serologic course

Answer 15

check powerpoint for graph - slide 16

Question 16

What does HBV DNA correlate with

Answer 16

HBV DNA correlates with risk of cirrhosis and HCC

Question 17

Natural progression of HBV infection

Answer 17

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

Question 18

What can acute infection - HBV progress to

Answer 18

> 90% of infected children progress to chronic disease

<5% of infected adults progress to chronic disease

Question 19

What can chronic infection progress to

Answer 19

• 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

Question 20

What can ongoing liver injury lead to

Answer 20

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

Question 21

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

Answer 21

• 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

Question 22

What are individuals with chronic hepatitis B at risk of developing

Answer 22

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

Question 23

Chronic HBV treatment

Answer 23

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

Question 24

Course of hepatitis B infection

Answer 24

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

Question 25

HBV - humoral response

Answer 25

- 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

Question 26

Hep C virus

Answer 26

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

Question 27

Hep C pathogenesis

Answer 27

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

Question 28

HCV - why chronicity

Answer 28

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

Question 29

HCV interference with immune response

Answer 29

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 ```

Question 30

IL28B

Answer 30

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

Question 31

Will chronic HCV always cause cirrhosis

Answer 31

- Only moderate and severe | - Dependent on age, gender(male more likely), alcohol, HIV, HBV

Question 32

Examples of antivirals used in curative treatment of HCV

Answer 32

- NS3/4A protease inhibitors - NS5A inhibitors - NS5B polymerase inhibitors

Question 33

Examples of NS3/4A protease inhibitors

Answer 33

- Grazoprevir | - Paritaprevir

Question 34

Examples of NS5A inhibitors inhibitors

Answer 34

- Ledipasvir (1, 4-6) | - Ombitasvir (1)

Question 35

NS5B RNA polymerase inhibitors

Answer 35

- Sofosbuvir (1-4) | - Dasabuvir(1)

Question 36

Genotype 1

Answer 36

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