Infectious Causes of Hepatitis Flashcards
acute viral hepatitis presents with
- non-specific flu like symptoms
- jaundice
- dark urine
- pale faeces
chronic viral hepatitis presents as
- general malaise
- cirrhosis, liver cancer
early exposure to acute viral hepatitis (HAV, HEV) results in
- less severe acute disease (not mounting as strong an immune response)
- higher rates of chronic infection
Hep A belongs to what family of viruses?
Picornaviridae (polio, rhinoviruses)
What is the structure of HAV?
- non-enveloped - resistant to stomach acid, dessication, outside environements
- +ssRNA
- 30nm, 7500nt encode single polyprotein
- single serotype worldwide
- replicates in cell culture tf able to produce vaccines
What is the HAV (+HEV) life cycle?
- transmitted from bile or faeces into food/water
- ingested
- replicates in intestinal epithelia
- travels through blood to liver
- replicates in liver
- gets into bile and faeces
ALT indicates
presence of replicating virus
How is acute viral hepatitis diagnosed?
- determine acute vs chronic/past
- serological tests (ELISA)
- IgM Ab to viral proteins (acute)
- reactive 1-2wks post-infection
- IgG Ab to viral proteins (convalescent)
- rising titre confirms acute
- IgM Ab to viral proteins (acute)
- NA tests (PCR) on blood/faeces (not as helpful with timing infection)
What is the incubation period of HAV?
- Average: 30 days
- Range: 15-50 days
HEV belongs to which family?
- Hepeviridae
What is the structure of HEV?
- non-enveloped but more fragile than HAV (doesn’t survie environment as well)
- icosahedral
- 30nm (small, similar to HAV)
- +ssRNA (like HAV)
- 7.7kb (similar size to HAV)
What is the incubation period of HEV?
- Average: 40 days
- Range: 2-10 weeks
How is HEV diagnosed?
- serology - ELISA for IgM and IgG
- NA assays (PCR) of serum and faeces
- Immune EM
- recently cutltured in vitro - candidate for vaccines
Which hepatitis virus has the highest risk of perinatal transmission?
HBV 30-50%
What is the structure of HBV?
- double-walled:
- outer envelope
- inner capsid
- also exists as incomplete envelope-only particles that are non-infectious
- HBsAg only
- dsDNA with an incomplete segment
- carries DNApol and RNA primer
How does HBV replicate?
- infects predominantly hepatocytes
- core enters nucleus and the ssDNA gap is ‘repaired’
- forms covalently closed circular DNA episome
- cccDNA acts as template for pregenome RNA
- encodes core, precore proteins and polymerase
- pregenome RNA form an encapsulated structure with polymerase
- reverse transcribed into DNA forming a new core particle
- DNA core particle can re-enter nucleus to amplify copies of ccDNA or assemble surface proteins via RER-golgi and bud off to infect
What is the life cycle of HBV (and HDV and HVC)?
- transmitted by blood, semen, exudates, secretions
- sex, close contact, or injection
- penetrates mucosal epithelia
- finds its way into blood
- replicates in hepatocytes of liver
How is HBV transmitted?
- perinatally by HBeAg positive in high prevalence populations
- sexual transmission - sex workers, homosexuals
- parenteral - IVDA, health workers
What is the incubation period of HBV?
- Average: 60-90 days
- Range: 45-180 days
infection with HBV at <5 years results in
- fewer acute symptoms - jaundice in less than 10%
- higher rates of chronic infection - 30-90%
What are the HBV sequelae?
- chronic carrier (HBsAg+)
- immune mediated liver damage
- cirrhosis
- liver failure
- primary hepatocellular carcinoma
- most common cause of liver cancer
What are the diagnostic markers used in HBV?
- HBsAg - general marker of infection
- anti-HBs Ig - recovery, immunity, or vaccination
- anti-HBc IgM - acute infection (rising titre)
- anti-HBc IgG - past or chronic infection
- HBeAg - active replication
- anti-HBe Ig - no longer replicating but can be sAg +ve from integrated HBV
- HBV-cccDNA - active replication
What are the current HBV antivirals?
- pegylated IFN-a
- nucleoside and nucleotide analogues
- lamivudine, entecavir
- adefovir, tenofovir
How does HDV infect?
- co-infection with HBV
- HBV provides sAg protein, in which HDV resides
- sAg allows HDV passage into hepatoctes
What is the structure of HDV?
- within HBsAg
- 70% self-complimentary ssRNA (viroid)
- produces delta antigen (core of viral particle)
What are the clinical features of HBV-HDV coinfection?
- severe acute disease
- low risk of chronic infection
- this is opposite to superinfection, where HBV infects first, then HDV
What are the clinical features of HBV-HDV superinfection?
- superinfection = HBV first, then HDV
- develop chronic HDV infection
- high risk of sever chronic liver disease
What family does HCV belong to?
Flavivirus
What is the structure of HCV?
- ss linear +RNA genome in nucleocapsid core
- high mutation rate and genotype diversity
- Aus: 3a, 1a, 1b, 2
- enveloped - E1 and E2 glycoproteins
- forms a polyprotein that is cleaved by non-structural protease
How does HCV replicate?
- associates with lipid and enters hepatocytes via lipid receptors or ones that interact with the envelope proteins
- enters via endosome, uncoated –> release RNA
- RNA targets ER where its translated
- produces -ssRNA to increase +ssRNA and tf proteins
- highly error-prone = mutations
- viruses leave via excocytosed vesicles into blood
- can be cell-cell transmission between hepatocytes
Telapravir and Boceprevir target
NS3, the protease that cleaves the HCV polyprotein
What is the incubation period of HCV?
- Average: 6-7 weeks
- Range: 2-26 weeks
What are the clinical features of HCV?
- jaundice is less common (30-40%)
- 70% risk of chronic hepatitis
- 70-90% risk of persistent infection
-
no protective Ab response is detected
- tf vaccines difficult
What are the HCV sequelae?
- 70-90% become chronic carriers
- liver fibrosis, cirrhosis, and failure
- primary HCC, often in conjunction w/HBV
- 170-300m carriers
- 5% lifetime mortality
What antivirals are used in HCV?
early (effectiveness dependent on IL28B gene):
- pegylated IFN-a (significant side effects ie fever)
- ribavirin (nucleoside inhibitor, not v effective)
new:
- direct acting antivirals (protease inhibitors that target NS3):
- boceprevir, telaprevir
- life cycle inhibitors
- entry, translation, post-processing, replication, assembly
- nucleotide analogue + protease inhibitor, -IFN-a
- highly curative for GT1, developing for GT3
