109 - Viral Hepatitis 1 and 2 Flashcards by Jack Cuthbertson

Cause of jaundice

Hyperbilireubinaemia

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Type of cancer that hepatitis can lead to

Hepatocellular carcinoma

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Effect of hepatitis viruses on host cells

Cytopathic (cause pathology), but not cytolytic (don’t lyse host cells)

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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

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Is there any cross-protection between hepatitis viruses?

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Enteric hepatitis viruses

Hep A and E

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Chronic hepatitis viruses

Hep B, D and C

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How are hep B, C and D transmitted?

Percutaneously, permucosally

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How to diagnose acute hepatitis 1 2

1) Serological tests (EG: ELISA) 2) Nucleic acid tests (EG: PCR). This is less effective than ELISA.

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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

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Hepatitis A viral family

Picornaviridae

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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

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Serotypes of hep A

Single serotype worldwide. All viral strains elicit the same antibody response.

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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

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Fulminant infection

Extremely-rapid onset

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A spike in what coincides with hepatitis symptoms?

Liver enzyme ALT (alanine aminotransferase, coincides with damaged liver)

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Hep A incubation period

Average 30 days.15-50 day range

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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%

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Hep A symptoms

Jaundice, vomiting, pale faeces, dark urine

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Hep A complications

Fulminant hepatitis (rarely), cholestatic hepatitis

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Chronic sequelae of hep A and E

None

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Typical serological course of hep A infection

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Length of hep A symptoms

2-3 weeks

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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

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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

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)