Infectious Causes of Hepatitis

Question 1

acute viral hepatitis presents with

Answer 1

• non-specific flu like symptoms
• jaundice
• dark urine
• pale faeces

Question 2

chronic viral hepatitis presents as

Answer 2

• general malaise
• cirrhosis, liver cancer

Question 3

early exposure to acute viral hepatitis (HAV, HEV) results in

Answer 3

• less severe acute disease (not mounting as strong an immune response)
• higher rates of chronic infection

Question 4

Hep A belongs to what family of viruses?

Answer 4

Picornaviridae (polio, rhinoviruses)

Question 5

What is the structure of HAV?

Answer 5

• 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

Question 6

What is the HAV (+HEV) life cycle?

Answer 6

• 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

Question 7

ALT indicates

Answer 7

presence of replicating virus

Question 8

How is acute viral hepatitis diagnosed?

Answer 8

• 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
• NA tests (PCR) on blood/faeces (not as helpful with timing infection)

Question 9

What is the incubation period of HAV?

Answer 9

• Average: 30 days
• Range: 15-50 days

Question 10

HEV belongs to which family?

Answer 10

• Hepeviridae

Question 11

What is the structure of HEV?

Answer 11

• 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)

Question 12

What is the incubation period of HEV?

Answer 12

• Average: 40 days
• Range: 2-10 weeks

Question 13

How is HEV diagnosed?

Answer 13

• serology - ELISA for IgM and IgG
• NA assays (PCR) of serum and faeces
• Immune EM
• recently cutltured in vitro - candidate for vaccines

Question 14

Which hepatitis virus has the highest risk of perinatal transmission?

Answer 14

HBV 30-50%

Question 15

What is the structure of HBV?

Answer 15

• 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

Question 16

How does HBV replicate?

Answer 16

• 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

Question 17

What is the life cycle of HBV (and HDV and HVC)?

Answer 17

• transmitted by blood, semen, exudates, secretions
  
  • sex, close contact, or injection
• penetrates mucosal epithelia
• finds its way into blood
• replicates in hepatocytes of liver

Question 18

How is HBV transmitted?

Answer 18

• perinatally by HBeAg positive in high prevalence populations
• sexual transmission - sex workers, homosexuals
• parenteral - IVDA, health workers

Question 19

What is the incubation period of HBV?

Answer 19

• Average: 60-90 days
• Range: 45-180 days

Question 20

infection with HBV at <5 years results in

Answer 20

• fewer acute symptoms - jaundice in less than 10%
• higher rates of chronic infection - 30-90%

Question 21

What are the HBV sequelae?

Answer 21

• chronic carrier (HBsAg+)
• immune mediated liver damage
• cirrhosis
• liver failure
• primary hepatocellular carcinoma
  
  • most common cause of liver cancer

Question 22

What are the diagnostic markers used in HBV?

Answer 22

• 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

Question 23

What are the current HBV antivirals?

Answer 23

• pegylated IFN-a
• nucleoside and nucleotide analogues
  
  • lamivudine, entecavir
  • adefovir, tenofovir

Question 24

How does HDV infect?

Answer 24

• co-infection with HBV
  
  • HBV provides sAg protein, in which HDV resides
  • sAg allows HDV passage into hepatoctes

Question 25

What is the structure of HDV?

Answer 25

* within HBsAg * 70% self-complimentary ssRNA (viroid) * produces delta antigen (core of viral particle)

Question 26

What are the clinical features of HBV-HDV **coinfection**?

Answer 26

* severe acute disease * low risk of chronic infection * *this is opposite to superinfection, where HBV infects first, then HDV*

Question 27

What are the clinical features of HBV-HDV **superinfection**?

Answer 27

* superinfection = HBV first, then HDV * develop chronic HDV infection * high risk of sever chronic liver disease

Question 28

What family does HCV belong to?

Answer 28

Flavivirus

Question 29

What is the structure of HCV?

Answer 29

* 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

Question 30

How does HCV replicate?

Answer 30

* 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

Question 31

Telapravir and Boceprevir target

Answer 31

NS3, the protease that cleaves the HCV polyprotein

Question 32

What is the incubation period of HCV?

Answer 32

* Average: 6-7 weeks * Range: 2-26 weeks

Question 33

What are the clinical features of HCV?

Answer 33

* 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

Question 34

What are the HCV sequelae?

Answer 34

* 70-90% become chronic carriers * liver fibrosis, cirrhosis, and failure * primary HCC, often in conjunction w/HBV * 170-300m carriers * 5% lifetime mortality

Question 35

What antivirals are used in HCV?

Answer 35

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