109 - Viral Hepatitis 1 and 2 Flashcards
Cause of jaundice
Hyperbilireubinaemia
Type of cancer that hepatitis can lead to
Hepatocellular carcinoma
Effect of hepatitis viruses on host cells
Cytopathic (cause pathology), but not cytolytic (don’t lyse host cells)
Different prognosis of hepatitis disease based on age of transmission
Younger exposure leads to less severe acute disease, greater likelihood of chronic diseaseOlder exposure leads to more severe acute disease, lesser likelihood of chronic disease
Is there any cross-protection between hepatitis viruses?
No
Enteric hepatitis viruses
Hep A and E
Chronic hepatitis viruses
Hep B, D and C
How are hep B, C and D transmitted?
Percutaneously, permucosally
How to diagnose acute hepatitis 1 2
1) Serological tests (EG: ELISA) 2) Nucleic acid tests (EG: PCR). This is less effective than ELISA.
ELISA tests for acute hepatitis1)2)3)
1) Over 90% sensitive, over 99% specific
2) IgM antibodies detectable at between 1-2 weeks after exposure.
3) Rising IgG titres indicates an acute infection
Hepatitis A viral family
Picornaviridae
Hep A virion characteristics1)2)3)
1) Non-enveloped, (+)ssRNA virus
2) 30nm particle, resistent to stomach acid
3) 7.5nt genome, coding for a single polyprotein
Serotypes of hep A
Single serotype worldwide. All viral strains elicit the same antibody response.
Hep A and hep E life cycles1)2)3)4)
1) Ingested from contaminated food or water
2) Replication in intestinal epithelia
3) Enters blood, replicates in the liver
4) Excreted via the bile canaliculi into faeces
Fulminant infection
Extremely-rapid onset
A spike in what coincides with hepatitis symptoms?
Liver enzyme ALT (alanine aminotransferase, coincides with damaged liver)
Hep A incubation period
Average 30 days.15-50 day range
Hep A symptoms by age group1)2)3)
1) Under 6 years, 10% show symptoms 2) Between 6-14 years, 40-50% 3) Over 14 years, 70-80%
Hep A symptoms
Jaundice, vomiting, pale faeces, dark urine
Hep A complications
Fulminant hepatitis (rarely), cholestatic hepatitis
Chronic sequelae of hep A and E
None
Typical serological course of hep A infection
Length of hep A symptoms
2-3 weeks
Hep A prevention and treatment1)2)3)4)
1) Sanitation
2) Pre-exposure (for travellers) or post-exposure (within 14 days of exposure) immunoglobulin
3) Supportive rehydration and nutrition
4) Vaccine
Hep A vaccine1)2)3)4)5)6)
1) Virus grown in a diploid cell culture
2) Inactivated whole virus with formalin
3) Alum adjuvant
4) 2-3 doses
5) Over 95% effective after 1 dose, ~100% after 2
6) Expensive to produce (because of diploid cells, testing for viral inactivation)
Hep E viral family
Hepeviridae.Formerly caliciviridae
Hep E virion characteristics1)2)3)4)
1) Non-enveloped, (+)ssRNA virus.
2) Icosahedral.
3) 7.7kb genome
4) Slightly more fragile virion than hep A
Differences between hep A and hep E distribution
Both affect Africa, central America, but hep E has a greater burden on Asia
Hep E epidemiology1)2)3)
1) Outbreaks associated with faecally-contaminated drinking water.
2) Minimal human-human transmission
3) Closely-related to a virus infecting pigs. Could be a zoonosis.
Hep E incubation period
Average 40 days.
2-10 week range
Hep E case fatality rate
~1-3% normally.
15-25% in pregnant women
Hep E typical serological course
Hepatitis viruses that can be sexually-transmitted
All, though hep B is the most likely to be transmitted
Hepatitis viruses that can be transmitted through intravenous drug use
Hep B and C
Proportion of Australian intravenous drug users who have hep C
50-60%
Hep B virion structure
Enveloped, with hep B surface antigen in envelopeViral DNA within a core (leading to double-walled structure in an electron micrograph)HBsAg can form VLPs
Hep B genome1)2)3)4)
1) 3kb relaxed circle of dsDNA
2) Viral polymerase on 5’ end of (-) strand
3) 2 12bp short direct repeats
4) 18nt ssRNA cap on 5’ end of (+) strand
HBeAg
A variant of the core protein, which has the pre-C region included
HBcAg
Hep B core protein (missing pre-C region, which would turn it into HBeAg
Life cycle of hep B, C, D1)2)3)4)
1) Contact via blood, sexual fluids
2) Virus penetrates intestinal epithelia (does not replicate here like hep A and E do)
3) Enters blood, travels to liver.
4) Replication in hepatocytes
Concentrations of hep B virus in body fluids1)2)3)
1) High - Blood, serum, wound exudates 2) Moderate - Semen, vaginal fluid, saliva 3) Low - Urine, faeces, sweat, tears, breast milk
Role of hep B pre-core
Essential for production of replication-competent viruses
Perinatial hep B transmission
Pregnant women who are HBeAg positive have a much higher risk of transmitting virus to child. Perinatal is the main source of transmission in high-prevalence areas
Hep B incubation period
Average 60-90 days 45-180 day range
Hep B different proportions of clinical jaundice based on age
Under 5 years, under 10% develop symptomsOver 5 years, 30-50%
Hep B case fatality rate
0.5-1%
Hep B chronic infection rate
Exposure when under 5 years - 30-90% chronic illness Exposure when over 5 years - 2-10%
Hep B mortality from chronic liver disease
15-25%
Two types of cirrhosis
Compensated and decompensated. Decompensated leads to death
Acute hep B typical serological course
Chronic hep B typical serological response
Hep B sequelae1)2)
1) Immune-mediated liver damage, leading to cirrhosis, maybe primary hepatocellular carcinoma
2) Most-common cause of liver cancer
Number of carriers of hep B worldwide
500 million
Complication of end-stage liver disease
Abdominal ascites
Proportion of hep B patients that develop hepatocellular carcinoma
2-10%
Cause of hepatocellular carcinoma
Random integration of hep B genome. Repeated destruction and regeneration of hepatocytes can lead to accumulation of chromosomal damage
General biomarker for hep B infection
HBsAg
Biomarker for recovery from hep B, or vaccination
anti-HBsAg Ig
Marker of acute hep B infection
Anti-HBsAg IgM
Marker of chronic or past hep B infection
Anti-HBsAg IgG
Marker of current hep B viral replication
HBeAg, hep B DNA
Biomarker that indicates that hep B is no longer replicating
Anti-HBeAg Ig
Hep B vaccine 1)2)3)
1) Subviral particles purified from yeast
2) Alum adjuvant
3) 2-3 doses
Hep D viral family
Deltaviridae
Hep D characteristics 1) 2) 3)
1) 70% complementary ssRNA genome
2) Only encodes a delta protein, which surrounds genome,
3) Requires hep B infection
Different ways to be infected with both hep B and D1)2)
1) Coinfection - Exposure to hep B and D at the same time. Severe acute disease, low risk of chronic infection. 2) Superinfection - Exposure to hep D when already infected with hep C. Usually develop chronic hep D infection. High risk of severe, chronic liver disease
Proportion of global population infected with hep C
3%
Proportion of hep C infections that occur through injecting drug use
80%
Proportion of hep C patients that develop chronic infection
70%
Hepatitis virus that can be initially asymptomatic
Hep C
Can hep C be cleared?
Yes. 30% clear the virus
Leading indicator for liver transplantation
Hep C infection
Hepatitis virus without a vaccine
Hep C
Hep C viral family
Flaviviridae
Mutation rate of hep C
Greater than that of HIV
Immunity against hep C
Very poor. Carriers can be superinfected with more than one strain of hep C
Is hep C culturable?
Not until recently. One strain can now be cultured in cells
Hep C virion characteristics1)2)3)4)5)
1) Double lipid membrane
2) E1E2 glycoprotein envelope dimer
3) Capsid
4) +ssRNA genome
5) Cholesterol droplet within envelope
Organisation of HCV genome1)2)3)4)
1) 9.4kb genome
2) 5’ UTR IRES
3) 5’ end of genome has structural proteins. 3’ end has nonstructural proteins
4) Encodes a polyprotein
HCV RDRP
NS5B
Receptors used by HCV
CD81, SR-BI, , Claudin-1, OCLDN, LDL-R.Complex series of receptors
Hep C incubation period
Average 6-7 weeks2-26 week range
Proportion of HCV patients that develop jaundice
30-40%
Proportion of HCV patients that develop chronic hepatitis
70%
Proportion of hep C patients that are chronic carriers
70-90%
Hepatitis virus that is hard to resolve using transmission electron microscopy
Hep C
Hep E common symptoms in adults
100% get jaundice.
100% get malaise
Hep C host cells
Kupfer cells, hepatocytes.
When is hep E secreted in faeces?
2 weeks before, 1 week after symptoms
Enteric hepatitis which can’t be treated with IV antibodies
Hep E
Big source of hep B genome mutations
Reverse transcription of genome
Strategies used by hep B to wnsure persistence
1
2
3
1) HBeAg - solible and secreted protein, both a tolerogen (perinatal transmission) and might regulate host immune system
2) HBsAg - Divers anti-HBs antibodies
3) HBV cccDNA - Major transcriptional template that persists in host cells. REsistant to nucleoside analogue therapy
Good hep B biomarker for active replication of escape mutants
Hep B DNA
HBV current antiviral drugs
1
2
1) Pegylated IFNa (for HBeAg + carriers)
2) Nucleoside/nucleotide analogues (low rate of viral clearance. Relapse almost inevitable)
Response rate of HBV infections to pegylated IFN
30-40%
Examples of anti-HBV nucleoside/nucleotide analogues, and basic function
1
2
3
4
1) 3TC (Lamivudine), Entecavir
2) Adefovir, Tenofovir (nucleoside analogues)
3) Target polymerase functions (RT)
4) Relapse almost inevitable after treatment stops
Enzymes involved in HCV genome replication
NSP5B, NS3
Clinical features of HCV
1
2
3
1) 30-40% develop clinical illness (jaundice)
2) 70-90% become chronic carriers
3) Cirrhosis, liver failiure, hepatocellular carcinoma
HCV antivirals
1
2
3
4
5
1) Ribavirin + pegylated IFNa (not always effective, can have serious side-effects)
2) Protease inhibitors (very effective when prescribed as a cotherapy with pegylated IFNa, ribavirin)
3) NS5B polymerase inhibitors
4) Cyclophilin B inhibitors (essential host cofactor)
5) NS5A inhibitors (IFN resistence gene)
Determinent of whether pegyylated IFNa therapy will be effective for HCV infection
IL28B gene genetic variation predicts response.
FDA-approved single-tablet anti-HCV drugs
1
2
1) Ledipsavir (NS5A inhibitor)
2) Sofosbuvir (NS5B inhibitor)
