Infection 6: Pathogenesis of viral hepatitis

Question 1

Acute hepatitis

Answer 1

More florid the attack, chronic sequelae less likely

Question 2

Chronic hepatitis

Answer 2

Abnormal LFTs and positive serological markers > 6 months

Question 3

Histological stage 1

Answer 3

Fibrous expansion of some portal areas

Question 4

Histological stage 3

Answer 4

Fibrous expansion of most portal areas with occasional portal to portal bridging

Question 5

Histological stage 4

Answer 5

Fibrous expansion of portal areas with marked bridging

Question 6

Histological stage 5,6

Answer 6

Cirrhosis probable or defined

Nodular fibrous scarring of the liver

Question 7

HBV replication

Answer 7

Replication of DNA genome by reverse transcription of RNA intermediate

Question 8

Commonest causes of liver damage and cirrhosis

Answer 8

Hepatitis

Question 9

Structure of virus

Answer 9

Viral DNA inside protein envelope

Lipid bilayer around it

Question 10

Viral life cycle

Answer 10

Viral particle infects liver cells

Binds to receptor

Goes into nucleus where DNA is linear

Repaired to become readable circular DNA

Remains in nucleus to be transcribed

Virus is assembled

New particle exocytosed

Neighbouring cells infected

Question 11

Damage

Answer 11

PAMP recognised by TLR3 leading to RIG-1 signalling

Interferon regulatory factors and NF-kB leads to interferon stimulating genes

This activates INF a/B

• down regulates viral protein synthesis
• inhibit viral replication
• promote adaptive immunity via MHC class 1 expression on APC
• activates NK, CD8 and dendritic cells
• activate cell death trough secretions of perforins

Question 12

Lack of HBV clearance

Answer 12

Evades detection of innate system
- ? cccDNA

Not recognised by hbost immune system

Interferes with expression of TLR

Question 13

HBsAb

Answer 13

Development of HBsAb provides life long immunity

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

Question 14

FAS ligand/ perforin

Answer 14

LATE: CD8 attaches to receptor on hepatitis cell
Leads to apoptosis so is cytopathic

EARLY: CD8 with IFN y/a doesn’t bind
Non-cytopathic

Question 15

Resolved infection

Answer 15

96% immunocompetent adults

Life long immunity

Polyclonal and multispecific intrahepatic CD8+ cells response

Early CD4+ primary contribute to synchronised influx HBV specific CD8+ cells resulting in viral clearance

Question 16

Persistent infection: age

Answer 16

HBeAg only antigen that crosses the placenta

• induces tolerance to HhcAg (most immunogenic)
• suppress immune mediated elimination of infected cells
• switches immune response to Th2

Question 17

Persistent infection: immunosuppresion- inadequate CMI

Answer 17

Weak/ narrow intrahepatic CD4+/CD8+ cell response

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

Question 18

Persistent infection

Answer 18

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

Foxp3 expressed on Tregs: suppress HBV specific T cell responses

Programmed death 1 receptor (CD28) upregulated- promote apoptosis thereby down regulate virus specific T cell

Cytotoxic T lymphocyte antigen 4: immune off switch when bound to CD80 or CD86 on the surface of antigen presenting cells

Question 19

Persistent infection: IL10

Answer 19

Down regulates antiviral immune responses
- CD4+ and CD8+ suppression with inhibition of IFN-y/a production

Attenuates inflammatory response but at cost of efficient antiviral immune responses

Question 20

Chronic HBV treatment

Answer 20

Pegylated interferon

Tenofovir/ tenefovir alafenamide

Entecavir

Cure defined by loss of HBsAg- happens only rarely

Question 21

Course of hepatitis B infection

Answer 21

Age at infection

Immunosuppression

Host immune response

HBV genotype and mutations

Coexisting risk factor: alcohol, HCV, HIV

Question 22

HBV key points

Answer 22

HBV evades innate immune responses

Early priming of CD4 cells –> CD8 cells activation

Humoral response late: no contribution to viral clearance by reduce viral spread
- HBsAb prevents reinfection

95% of immunocompetent adults clear the infection

90% neonates develop chronic infection

Question 23

Hepatitis C infection

Answer 23

RNA virus

Rapid rate of replication

80% develop chronic infection

No vaccine

Question 24

HCV high replication rate of viral antigen load

Answer 24

CD8+/CD4+ anergic/ exhausted: unable to proliferate/ secrete cytokines

Display normal immune responses to other viruses

Question 25

HCV high error rate of RNA dependent polymerase

Answer 25

Leading to mutations (quasispecies)

Escape neutralizing antibodies and cellular immune responses

Question 26

HCV proteins interfere with immune response

Answer 26

NS proteins inhibit innate immune reponses (recognition of TLR) through disruption of RIG-I signalling

Core protein down regulates IL-12 production

Question 27

HCV neutralizing AB

Answer 27

Core, envelope, NS3, NS4

Develops too slowly, too late, short lived inducing HCV escape mutations

Question 28

HCV key points

Answer 28

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 antiviral resulted in paradigm shift in HCV management