Enright hepatitis Flashcards
Describe the mechanism of hepatocyte injury in viral hepatitis B
*Infected hepatocytes present viral peptides on MHC-1 molecules which are recognised by CD8+ Cytotoxic T cells –> release of perforins, granzymes and induction of apoptosis via FAS/FAS-L pathway.
*Infected cells release inferferon-alpha which attracts natural killer cells –> directly cytotoxic + release of interferon-gamma which attracts macrophages and CTL’s.
*Hepatic dendritic cells can present viral peptides to CD4+ T cells via MHC-II –> release of inflammatory cytokines, enhance CTL activity and B cell activation.
It is important to note that HBV goes unrecongized by the innate immune response in the initial stages of infection –> This is because HBV is a DNA virus, and its viral genome does not easily trigger the recognition pathways associated with RNA viruses.
Morphological features of acute viral hepatitis
- ballooning degeneration of hepatocytes
- Spotty necrosis and apoptosis (eosinophilic councilmann bodies) throughout the lobule with lymphocytes and macrophages.
- Kuppfer cell hyperplasia
- Early fibrosis
- Severe cases
–> Congestion and hemorrhage
–> Necrosis around central vein
–> Intrahepatic cholestasis; liver has a yellowing appearance.
4 histological features of chronic viral hepatitis
- Inflammation around the portal triad
- Involvement of the limiting plate surrounding the portal triad –> can become inflamed or necrotic.
- Fibrosis with porto-portal fibrous bridging –> fibrosis extends between portal triads and can eventually lead to cirrhosis.
- Degradation and collapse of reticulin framework
Outline the immune phases in chronic HBV infection
1. Immune tolerant phase
–> Typically seen in children that were infected perinatally, the immune system does not target the virus, despite high HBV DNA.
–> May be asymptomatic with minimal liver inflammation and normal LFT’s
2. Clearance phase
–> The immune response against the virally infected hepatocytes ramps up, generally as part of natural progression of the infection.
–> symptoms of acute hepatitis
–> There is increased liver inflammation with raised LFT’s.
–> HBV DNA levels decline due to clearance of the virus.
3. Inactive carrier phase.
–> The virus is present in low levels, with low or undetectable HBV DNA levels.
–> Minimal inflammation and normal LFTs.
–> Asymptomatic
4. Reactivation phase
–> Typically due to immunocompromising factors such as cancer or HIV
–> Viral load rises due to increased viral replication (high HBV DNA)
–> Increased liver inflammation
–> Elevated LFTs
–> sings of acute hepatitis
Describe the MOA of pegylated-interferon alpha in HBV eradication
1.Halts viral replication
- It binds to interferon receptors on hepatocytes which activates the JAK-STAT pathway intracellularly.
- Downstream, this induces transcription of interferon-stimulated genes in the nucleus.
- This produces anti-viral proteins such as 2,5-oligoadenylate synthase
- These proteins inhibit viral replication by targeting viral RNA.
2. Immunomodulatory effects
- PEG-IFN-alpha activates natural killer cells and macrophages.
- It therefore promotes IFN-y release (from NK cells) which upregulates the CTL response.
- This helps eradicate the virus by enhancing the immune response against the virally infected hepatocytes.
Describe the MOA of nucleoside analogues in management of HBV
Lamivudine, Entecavir, Tenofovir
*The drug is phosphorylated to its triphosphate form by intracellular kinases.
*It is then competes with endogenous/natural nucleosides (such as cytosine or guanine) and is inserted into the growing DNA chain by HBV reverse transcriptase.
*The drug lacks the 3’ hydroxyl group.
*Without the 3’ hydroxyl group, the reverse transcriptase enzyme cannot add the next nucleotide, thus halting the elongation of the viral DNA and preventing further replication of the virus
This should therefore lower HBV levels
Describe the life cycle of hep B
-The virus attaches to the hepatocyte surface through the NTCP receptor using its HBsAg (Hepatitis B surface antigen), and it is endocytosed into the cell.
-Once inside the cell, the virus is uncoated, releasing the relaxed circular DNA (rcDNA) into the cytoplasm.
-The rcDNA is transported along microtubules to the nucleus, where it is converted into covalently closed circular DNA (cccDNA).
-cccDNA serves as a template for transcription, producing viral mRNA.
-The viral mRNA is translated into viral proteins in the cytoplasm, and new viral particles are assembled, forming immature virions.
-The immature virions are then packaged, and mature virions are formed, which can bud off from the hepatocyte and infect other cells.
-The cccDNA remains in the nucleus, establishing a persistent infection that can last for years.
Describe life cycle of HCV
-The hepatitis C virus (HCV) uses its envelope glycoproteins, E1 and E2, to bind to specific receptors on hepatocytes, including CD81, SR-B1, and CLDN1 (claudin-1).
-After binding, the virus is endocytosed and enclosed within an endosomal vesicle in the cytoplasm.
-The viral envelope fuses with the endosomal membrane, releasing the single-stranded RNA (ssRNA) genome into the cytoplasm.
-Once in the cytoplasm, the viral RNA acts as messenger RNA (mRNA) and is directly translated by the host cell’s ribosomes into a polyprotein. This polyprotein is cleaved by viral proteases (such as the NS3/4A protease) into individual functional proteins: structural proteins (e.g., for the viral capsid and envelope) and non-structural proteins (important for replication and assembly)
-The replication of the viral genome occurs in the cytoplasm, where the NS5B polymerase synthesizes new RNA genomes.
-New virions are assembled in the endoplasmic reticulum (ER) and Golgi apparatus, then released into the extracellular space via exocytosis
How does acute hepatitis cause dark urine and pale stool?
-Acute hepatitis can cause cholestasis; disruption in bile flow. This impairs the normal excretion of conjugated bilirubin into the bile ducts and reduces its flow into the intestines.
-Conjugated bilirubin enters the bloodstream instead of being excreted into the bile. This leads to hyperbilirubinemia
-Dark urine: The excess conjugated bilirubin in the blood is filtered by the kidneys and excreted in the urine, resulting in dark urine
-Pale stools: Since bilirubin is normally excreted into the intestines and converted by gut bacteria into stercobilin, a reduced flow of bile into the duodenum results in less stercobilin production. As a result, the stools appear pale or clay-colored due to the lack of this normal pigment.
Outline the classes of direct acting anti-virals and how each works in the management of HCV
(1) NS3/4A protease inhibitors
-Glecaprevir/ Grazoprevir
-Inhibit the cleavage of the newly translated viral polyprotein into structural and non-structural proteins.
(2) NS5A inhibitors
- Velpatasvir, Pibrentasvir/ Elbasvir/ Ledipasvir
- Inhibits the normal replication and assembly of new virions
(3) NS5B polymerase inhibitors
- Sofosbuvir
- Inhibits the normal replication cycle of the virus
Define acute liver failure
Rapid decline in liver function (hours to weeks) in someone without previous liver disease, characterized by:
-Jaundice
-Coagulopathy (INR >1.5)
-Hepatic encephalopthy
Typically occurs within 8 weeks of initial injury
Name 4 contra-indications to liver biopsy
(1) Bleeding diathesis (bleeding disorder/coagulopathy)
(2) Hemangiomas
(3) Hydatid cyst
(4) Severe ascites
(5) Infection at biopsy site
Name 4 complications of a liver biopsy
(1) Pneumothorax
(2) Hemorrhage
(3) Perforation of nearby structures e.g. gall bladder
(4) Infection
