Pathogenesis of viral hepatitis Flashcards
Viral hepatitis
- Subclinical
- Acute hepatitis: more florid the attack, chronic sequelae less likely
- Acute liver failure
- Chronic: abnormal LFTs and positive serological markers > 6 months
Histological staging of hepatic fibrosis
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
HBV - replication
- Replication of DNA genome by reverse transcription of RNA intermediate
HBV - recognition
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
HBsAb
- Development of HBsAb provides life long immunity
- Neutralising antibody - forms complex with HBSAg and prevents uptake by uninfected hepatocytes
What is the fas ligand
- Fas ligand is a type II transmembrane protein that belongs to the tumour necrosis factor
- Its binding with its receptor induces apoptosis
Resolved infection
- 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
Persistent infection
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+/
Effect of HBV X protein on antigen processing
- HBV X protein interferes with antigen processing and presentation - protects ccc DNA
Effect of Foxp3
Foxp3 (forkheadP3 transcription factor) expressed on Tregs - suppress HBV specific T cell responses
Programmed death-1 receptor
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
Cytotoxic T-lymphocyte antigen 4(CTLA4)(CD152)
- “Immune off” switch when bound to CD 80 or CD86 on the surface of antigen-presenting cells
Persistent infection: IL-10
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
Acute hep b virus infection with recovery typical serologic course
check powerpoint for graph - slide 16
Progression to chronic hep B virus infection - typical serologic course
check powerpoint for graph - slide 16
What does HBV DNA correlate with
HBV DNA correlates with risk of cirrhosis and HCC
Natural progression of HBV infection
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
What can acute infection - HBV progress to
> 90% of infected children progress to chronic disease
<5% of infected adults progress to chronic disease
What can chronic infection progress to
- 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
What can ongoing liver injury lead to
- 5 yr probability (8-20%) –> cirrhosis –> 25% decompensate in 5 yrs, 5yr survival 14-35% –> liver failure or liver cancer
What is chronic hepatitis B acute infection in adults generally accompanied by
- 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
What are individuals with chronic hepatitis B at risk of developing
- Significant risk for developing hepatocellular carcinoma(HCC), cirrhosis, or liver failure
- HCC or liver failure lead to liver transplantation or death
Chronic HBV treatment
- Pegylated interferon
- Tenofovir/tenofovir alafenamide
- Entecavir
- Cure defined by loss of HBsAg - happens only rarely
Course of hepatitis B infection
- Age at infection
- Immunosuppression
- Host immune response
- HBV genotype and mutations -
- Coexisting risk factor - alcohol, HCV, HIV
HBV - humoral response
- 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
Hep C virus
- RNA virus
- Rapid rate of replication
- 80% develop chronic infection
- No vaccine
Hep C pathogenesis
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
HCV - why chronicity
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
HCV interference with immune response
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
IL28B
- IL28B is involved in immune response to HCV
- 3 subtypes - CC, CT, TT
- People with CC have strongest immune response to HCV
Will chronic HCV always cause cirrhosis
- Only moderate and severe
- Dependent on age, gender(male more likely), alcohol, HIV, HBV
Examples of antivirals used in curative treatment of HCV
- NS3/4A protease inhibitors
- NS5A inhibitors
- NS5B polymerase inhibitors
Examples of NS3/4A protease inhibitors
- Grazoprevir
- Paritaprevir
Examples of NS5A inhibitors inhibitors
- Ledipasvir (1, 4-6)
- Ombitasvir (1)
NS5B RNA polymerase inhibitors
- Sofosbuvir (1-4)
- Dasabuvir(1)
Genotype 1
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
