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ATU > Hepatitis > Flashcards

Hepatitis Flashcards

1
Q

Describe the blood supply to the liver

  • which vessels supply it?
  • where does it drain back to the heart via?
A

Dual blood supply:

  • hepatic artery from the aorta - oxygenated blood from the general circulation
  • hepatic portal vein - deoxygenated blood from. The intestines containing nutrients
  • blood drains back to the heart via the vena cava
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2
Q

What is a hepatic sinusoid and what is its function?

A
  • a sinusoidal blood vessel (I.e. Fenestrated, discontinuous endothelium)
  • serves as location for the mixing of oxygen rich blood from hepatic artery and nutrient rich blood from portal vein
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3
Q

What does the liver have instead of a capillary network ?

A

Sinusoids surrounding hepatocytes

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4
Q

What structure do sinusoids lead to?

A

Central venules - the veins found at the centre of hepatic lobules

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5
Q

Which cell makes up the majority of the main parenchymal tissue of the liver ?
- percentage of the weight and mass ?

A

Hepatocytes

  • 60% weight
  • 80% mass
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6
Q

What is the Space of Disse ?

- what is its function?

A
  • separates hepatocytes from sinusoids
  • contains stellate cells - store fat/ fat sol vitamins
  • microvilli of hepatocytes extend in to this space allowing proteins and other plasma components to be absorbed from this space into hepatocytes
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7
Q

Which cells are involved in fibrosis of the liver?

A

Stellate cells

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8
Q

Stellate cells are involved in the storage of what ?

A

Vit A

  • in fibrosis when stellate cells damaged vit A storage drops
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9
Q

What is the role of hepatocytes?

A
  • met of carbs, fats, proteins
  • production of serum components
  • detoxification
  • bile production
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10
Q

Which proteins are produced by the hepatocytes?

A
  • albumin
  • fibrinogen
  • prothrombin clotting factors (NOT 3 and 4)
  • lipoproteins
  • ceruloplasmin
  • transferrin
  • complement
  • glycoproteins
  • structural proteins
  • intracellular enzymes
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11
Q

Which organelle within the hepatocyte are proteins synthesised?

A

Rough ER

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12
Q

What is the role of the smooth ER within Hepatocytes?

A

Secretion of proteins formed

*Hepatocytes have abundant smooth ER (most human cells have low levels)

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13
Q

What are triglycerides formed from in carb metabolism in hepatocytes ?

A

Fatty acids and glycerol

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14
Q

Where is the main site of gluconeogenesis?

A

Hepatocytes

  • synthesis of glucose from AAs and non-hexose carbs
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15
Q

What is glycogenesis?

A

Excess sugar taken up and sequestered rapidly in the liver and stored as glycogen

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16
Q

What is glycogenolysis?

A

Depolymerisation of glycogen when blood sugar levels drop, exporting glucose back to the blood

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17
Q

What is the process of synthesising glucose from AAs and non-hexose carbs ?

A

Gluconeogenesis

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18
Q

What are apoproteins and where are they synthesised?

A

Proteins which together with a prosthetic group forms a particular biochemical molecule e.g. Hormone or enzyme
- synthesises in hepatocytes (carbohydrate metabolism)

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19
Q

Where in the liver does fat metabolism occur?

A

Hepatocytes

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20
Q

What are bile acids derived from?

A

Cholesterol

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21
Q

Function of bile acids ?

A

Digestion and absorption of fat and fat solvable vitamins

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22
Q

What percentage of bile is excreted ?

A

5%

*95% recirculated back to the liver

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23
Q

Conjugation with what makes bile water soluble (and therefore able to be excreted in bile)?

A

Glucuronic acid in liver

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24
Q

Bilirubin is produced in the breakdown of what?

A

Senescent RBCs

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25
Q

Unconjugated bilirubin is bound to what?

A

Albumin

*considered conjugated when bound with glucuronic acid

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26
Q

How does hepatitis cause jaundice ?

A

Hepatocyte dysfunction means bilirubin is not conjugated with glucuronic acid and therefore is not water soluble and cannot be excreted in bile, therefore levels build up in serum causing yellow discolouring of skin, eyes etc

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27
Q

Conjugated bilirubin is deconjugated into urobilinogen by what in the intestine?

A

Colonic bacteria

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28
Q

The oxidation of what produces urobilin and stercobilin?

- what is their affect on faeces?

A

Urobilinogen

- colour faeces brown

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29
Q

What colours the urine yellow ?

A

Urobilinogen

- traces that are reabsorbed into the enterohepatic circulation and pass through the kidneys in to the urine

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30
Q

Diagnosistic blood results in acute hepatitis

ALT, albumin and bilirubin

A
  • raised alanine aminotransferase
  • decreased albumin
  • raised bilirubin
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31
Q

Which Ig is first to appear in hepatitis infection?

A

IgM

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32
Q

Which Ig remains detectable for life following hepatitis infection?

A

IgG

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33
Q

A patient has IgG against hep virus, but no detectable IgM. What does this suggest?

A

Either past infection or vaccination but no active infection

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34
Q

Which hepatitis viruses cause chronic hepatitis ?

A

B and C

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35
Q

Diagnostic methods in chronic hepatitis ?

A
  • ultrasound, CT, MRI - see if fibrosis or HCC
  • transient elastography - asses fibrosis
  • liver biopsy - assess necro-inflam. Grade and fibrosis stage
  • hepatic B and C serology
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36
Q

What is the role of the liver

A

Metabolism

Homeostasis

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37
Q

Which hepatitis viruses are enveloped ?

A

B
C
D

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38
Q

Which hepatitis viruses cause acute hepatitis ?

A

A and E

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39
Q

Which hepatitis viruses are transmitted enterically ?

A

A and E

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40
Q

What family does hepatitis A virus belong to?

A

Picornaviridae

Pico = small RNA= genome viridae= virus family

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41
Q

Which other viruses if HAV related to ?

A
  • Polio
  • Foot and Mouth
  • Rhinovirus
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42
Q

Describe the genome of HAV

A

Small, single stranded, positive sense, RNA genome

  • 7.5kb
  • group IV
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43
Q

What is VPg and what are its functions ?

A

‘Viral protein genome-linked’- protein that is covalently attached to 5’ end of + strand viral RNA

  • acts as primer during RNA synthesis (when uridylated by 3Dpol)
  • also has role in translation initiation where acts like 5’ mRNA cap
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44
Q

Which virus families is VPg seen in?

A

Picornviridae e.g. HAV

Calicviridae e.g. Norovirus/Norwalk virus

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45
Q

P1 region of HAV genome encodes what?

A

Structural proteins - VP1,2,3,4

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46
Q

Which regions if the HAV genome code for non structural proteins?

A

p2 and P3

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47
Q

What are IRES and what’s their function?

A

Internal ribosome entry site

  • allows cap independent initiation of translation
  • can initiate translation in the middle of the mRNA
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48
Q

Which domains are antigenic sites of HAV?

A

Exposed parts of VP1 and 3 on capsid surface

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49
Q

What process is the 3’ UTR and poly a tail in HAV genome important in ?

A

Negative sense strand synthesis in HAV

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50
Q

How many genotypes of HAV ?

A

6 all closely related

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51
Q

What is an open reading frame ?

A

Portion of DNA which when translated into amino acids contains no stop codons

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52
Q

Which hepatitis virus is characterised by being more severe on pregnant women ?

A

HEV

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53
Q

Which hepatitis virus is primarily water Bourne ?

A

HEV

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54
Q

How many ORFs does HEV have ?

A

3

55
Q

How many open reading frames does HAV have ?

A

1 large ORF

56
Q

Which ORF in HEV codes for none structural proteins ?

A

ORF 1

57
Q

Which ORF in HEV codes for structural proteins ?

A

ORF 2

58
Q

What does ORF 3 in HEV code for ? And what is its possible function ?

A

Small immunogenic phosphoprotein which associates with cytoskeleton
- suggests possible role in assembly

59
Q

Which hepatitis virus has a 5’m7G cap?

A

HEV

60
Q

How many genotypes are the of HEV and which are zoonotic ?

A

4

- 3 and 4 are zoonoses

61
Q

How many genotypes of HAV ? Which are human and which are simian ?

A

7

  • 1-3 and 7 = human
  • 4-6 = simian
62
Q

What is the function of the ESCRT system ?

A

Enable mode of membrane remodelling that results in membranes budding away from the cytoplasm

  • MVB biogenesis
  • cellular abscission
  • viral budding
63
Q

Which accessory proteins are associated with the ESCRT system ?

A

TSG101 (HEV, ORF3)

ALIX (HAV, VP2)

64
Q

Which hepatitis virus has an all coding genome ?

A

Hep B

65
Q

What does the P ORF of hepatitis b encode ?

A

Polymerase

* makes up 3/4 of genome

66
Q

What does S ORF of hepatitis B Virus encode ?

A

Viral surface envelope protein - HBsAG

*surface antigen of HBV, indicates current infection

67
Q

What does the C ORF of HBV encode ?

A
  • HBcAg - viral nucleocapsid - core antigen
  • HBeAg - e antigen
  • together a marker of active replication, antibodies to these antigens suggests declining replication
68
Q

What does the presence of HBeAg indicate ?

A

Active viral replication, suggests the person can likely transmit the virus
- tells us whether they are infectious

69
Q

Which is secreted, HBeAg or HBcAg?

A

HBeAg (e antigen) - circulates in the blood

- whereas core antigen is detected after liver biopsy

70
Q

Which ORF in the HBV virus genome codes for the X antigen (HBxAg)?

A

X ORF

71
Q

What is the role of HBxAg?

A
  • control of the cell cycle

- associated with development of HCC

72
Q

Where is the polymerase located on HBV genome ?

A

Covalently linked to 5’ end of negative DNA strand

73
Q

How long can HBV remain outside the body and retain infectivity?

A

7 days

74
Q

What % of HBV adult cases leads to chronic disease ?

A
75
Q

First line NICE recommended treatment for chronic HBV ?

A

Peginterferon alpha 2a (48weeks)

76
Q

Second line treatment for HBV chronic infection

A

Lamivudine, adefovir diproxil

77
Q

Why is lamivudine used in HBV patients as prophylaxis for immunosupression only if lasting

A

More likely to result in resistance than adefovir diproxil or entecavir

78
Q

Why does HDV require co infection with HBV for replication ?

A

Uses HBsAg as its own coat virion

79
Q

Which is the only animal virus known to have circular RNA ?

A

HDV

80
Q

Define RNA editing

A

Site-specific modification of RNA sequence from that of its template by mechanisms other than splicing

81
Q

Why is RNA editing critical in HDV lifecycle ?

A

Creates two forms of delta antigen small and large

  • HDAg-S supports viral RNA replication
  • HDAg-L is required for virion packaging but inhibits replication
  • both these functions necessary for successful infectious virion to be created thus RNA editing is essential
82
Q

What is the mechanism by which RNA editing is carried out in HDV ?

A

Adenosine Deamination

83
Q

What is George barker virus ?

A
  • related to HCV
  • human lymphotrophic virus, rarely causes disease
  • protective effect against HIV replication
84
Q

What is non-primate hepacivirus?

A
  • closely related to HCV

- mild hepatitis in horses

85
Q

How many ORFs in HCV genome ?

A

1

86
Q

How many structural proteins coded for by HCV genome? Name them

A

3 maybe 4

- core, E1, E2, maybe p7

87
Q

Which non structural protein coded for in HCV genome exhibits self cleavage ?

A

NS2

*cleaves its self from NS3 so NS3 can go on to cleave rest of NS proteins

88
Q

Which non structural proteins in HCV genome form a bifunctional enzyme with protease and helicase activity ?

A

NS3 and NS4A

89
Q

What is the function of NS5B in HCV genome ?

A

RdRp

90
Q

What is the expected function of p7 in HCV genome ?

A

Forms virporin

91
Q

What are structural proteins in HCV genome cleaved by?

A

HOST signal peptidases

92
Q

Likely host cell receptors for HCV entry?

A
  • LDL Receptor

- CD81

93
Q

Which hepatitis virus has no vaccine ?

A

HCV

94
Q

Which genotype of HCV is most common across the world ?

A

G1

95
Q

What is the HCV genotype distribution in the UK ?

A

G1:G3 50:50

*G3 driven by Pakistan > UK

96
Q

Which genotype is particularly resistant ?

A

G3

97
Q

Risk factors associated with fibrosis progression in HCV infection (7)

A
  • make sex
  • duration of infection
  • acquisition of HCV >40y
  • long term alcohol abuse
  • long term immunosupression e.g. HIV
  • HBV co infection
  • non response to antivirals
98
Q

Mechanisms of liver damage in HCV infection? (4)

A
  • immune mediated cytolysis
  • hepatic steatosis
  • oxidative stress
  • insulin resistance
99
Q

5 pathways that must be dysregulated for HCC

A
  • block apoptosis
  • increase cell cycle
  • vascularisation
  • upregulate gene expression for adherence
  • upregulation to proliferate through cell cycle
100
Q

Which proteins in HCV genome are involved in the development of HCC?

A

Core,NS3, NS5A and NS5B

101
Q

First line treatment for HCV

A
  • 1 x week subcut peginterferon alpha-2a
    AND
  • 1 x daily oral ribavirin

*48weeks G1,4-6, 24weeks G2 and 3

102
Q

Second line treatment for HCV

A

Boceprevir or telapevir

In combo with pegIFN-a-2a and ribavirin

*G1 or compensated liver disease

103
Q

What percentage of HCV infections lead to HCC?

A

1-5%

104
Q

How do CypA inhibitors work in HCV ?

A

Antiviral and anti inflammatory effects

105
Q

Name the CypAi in phase III development

A

Alispovir

106
Q

What is the interferon free antiviral regime identified in the INFORM-1 study for treatment of HCV ?

A
  • polymerase inhibitor: nucleoside NS5Bi (mericitabine)

- protease inhibitor: NS3i (Danoprevir)

107
Q

Which NS5Bi class have high resistance barrier ?

A

Nucleoside inhibitors

108
Q

What is the role of p7 in HCV

A

Dissipates ionic gradient in lysosomes to prevent destruction of virus by acidic pH

109
Q

What type of drug is ribavirin?

A

Nucleoside NS5B polymerase inhibitor

110
Q

Name the targets of DAA in HCV

A
  • NS5B polymerase inhibitor
  • NS2i protease inhibitor
  • NS3/4A protease inhibitor
  • p7i
  • NS5Ai
111
Q

Function of NS2 in HCV ?

A

Virus assembly and release

112
Q

Which NS proteins in HCV block induction of IFN-beta expression?

A

NS3/4A

Therefore blocks innate immune response

113
Q

Which non structural protein in HCV forms the replication complex ?

A

NS4B

114
Q

Which NS protein in HCV has 3 domains separated by low complexity sequences ?

A

NS5A

115
Q

Which phosphorylation sites in NS5A in HCV are important for replication ?

A

S222 and s225

116
Q

What class of antiviral is daclatasvir?

A

NS5Ai - DAA

117
Q

Function of NS5B in HCV

A

RdRp

118
Q

What class of antiviral is sofusbuvir?

A

Nucleoside NS5B polymerase inhibitor - DAA

119
Q

How was an infectious molecular clone of HCV first made ?

A
  • reverse genetics
  • optimised to be expressed in E. coli
  • T7 promoter
  • linearised
  • RNA replica injected in to chimps
120
Q

What is a sub genomic replicon of HCV

A
  • HCV genome with structural proteins taken out - so left with cassette of proteins needed for RNA replication
  • still capable of autonomous replication and production of infectious particles
121
Q

What family and genus is HCV in ?

A

F: flaviviridae
G: Hepacivirus

122
Q

Paper describing HCV replicons

A

Woerz et al

123
Q

The HCV replicon is bicistronic, what does it encode ?

A
  1. Neo gene

2. HCV replicate genes (NS3-NS5B)

124
Q

What is G418?

A

Neomycin analogue

*resistance to this encoded by the neo gene in HCV sg replicons, allowing selection of RNA expressing cells

125
Q

Which parts of virus life cycle do replicons allow us to study ?

A

Genome replication and translation

126
Q

Problems with HCV sub genomic replicons (4)

A
  • only work in Huh7 cells - highly transformed, can’t study oncogenesis as already tumour cells
  • only allows study of replication and translation and not internalisation or egress
  • subsequent full length replicons didn’t work
  • contra adaptive mutations hampered study
127
Q

What is the GND mutants of HCV ?

A

Inactive NS5B polymerase so can’t replicate

128
Q

Which UTR in HCV genome interacts with cellular factor ?

A

5’ end

129
Q

Describe the 3 domains of the 3’ UTR in HCV genome

A
  • conserved X tail
  • short variable region
  • poly U/UC Tail
130
Q

Role of miRNA 122 in human cells

A
  • liver specific
  • regulates gene expression, chol. Met., iron homeostasis
  • needed for HCV replication
131
Q

Name of experimental drug which targets miRNA122 in HCV treatment ?

A

Miravirsen

132
Q

Role of miRNA in HCV replication ?

A

Binds to and protects 5’ end of viral RNA genome and shields from degradation by exonuclear digestion

133
Q

Genotype specificity of non nucleoside protease inhibitors of HCV

A

G1

134
Q

Which treatments are actually most recommended but are not covered by the NHS ?

A

Sofusbuvir (NS5B) and ledipavir (NS5A)

ATU (3 decks)

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