Micro Test 4: Hepatitis

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Micro Test 4: Hepatitis
2013-02-06 00:22:15
Micro Test Hepatitis

Micro Test 4 Hepatitis
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  1. HAV:
    • Source- feces, blood
    • Transmission- fecal-oral
    • Tx- none (suppurative)
  2. HBV:
    • Source- blood, fluids
    • Transmission- percutaneous, permucosal
    • Tx- lamivudine/adefovir, IFN
  3. HCV:
    • Source- blood, fluids
    • Transmission- percutaneous, permucosal
    • Tx- IFN, ribavirin, telaprevir or boceprevir
  4. HDV:
    • Source- blood, fluids
    • Transmission- percutaneous, permucosal
    • Tx-  Same as HBV
  5. HEV:
    • Source- feces (human and animal)
    • Transmission- fecal-oral
    • Tx- None (supportive)
  6. Which two types of Hepatitis viruses have fecal- oral transmission?
    HAV, HEV
  7. Which three types of hepatitis cause chronic infxn?  What other thing do they also increase risk for?
    • HBV, HCV, HDV
    • They increase the risk for Liver CA
  8. How do you diagnose HAV?
    HAV Ab
  9. How do you diagnose HBV?
    • HBsAg
    • HBcAb
    • HBV DNA
  10. How do you diagnose HCV?
    • HCV Ab
    • HCV RNA
  11. How do you diagnose HDV?
    • HDV Ab
    • Delta Ag
  12. How do you diagnose HEV?
    • HEV Ab
    • HEV RNA
  13. Which types of Hepatitis can be prevented with a vaccine?  What types of vaccines?
    • HAV- formalin inactivated  virus
    • HBV- Yeast-expressed HBsAg (also prevents HdV since you must have HBV to have HDV)
    • HEV- Bacteria expressed coat protein)
  14. Clinical Symptoms of Hepatitis are they same, regardless of the cause (e.g. A, B, C, other viruses, toxins.)  Name them.
    • Nause, vomiting
    • Abdominal pain
    • Loss of appetitie
    • Fever
    • Diarrhea
    • Light (clay) colored stools
    • Dark urine
    • Jaundice (yellowing of eyes, skin)
  15. Hepatitis shows elevation of what two enzymes
    Serum aminotransferases (AST, ALT)
  16. Viral hepatitis symptoms are due to?
    Immune attack on infected liver, not directly due to viral infxn
  17. Risk of post-exposure infxn is greatest to what form of hepatitis in healthcare workers?
    HBV (6-30%)
  18. Post exposure prophylaxis for healthcare workers:
    • HIV- antiviral cocktail
    • HBV- Vaccine, HBIG
    • HCV- none
  19. Name 2 other hepatotropic viruses and what they causes besides hepatitis.
    • Flaviviruses- Yellow Fever Virus (YFV), Dengue (Denv)
    • Retroviruses- Primary Biliary Cirrhosis
    •          Destruction of small intrahepatic bile ducts
    •          Anti-mitochondrial Ab (AMA)
    •                    Human betaretrovirus
    •                    High homology to murine mammary tumor virus (MMTV)
  20. Anti-mitochondrial Abs are found in?  They have a high homology to?
    • Primary Biliary Cirrhosis
    • High homology to murine mammary tumor virus (MMTV)
  21. Name the 2 enterically transmitted hepatitis viruses
    • HAV
    • HEV
  22. HAV Structure:
    Type of virus?
    Stable to?
    Name 3 other viruses in this family.
    • Picorna virus (small RNA)
    • Non-enveloped
    • Stable to low pH, detergent, drying, heat
    • Same family as polio, rhino, Coxsackie viruses
  23. Form of hepatitis stable in low pH, detergent, and drying
  24. How many serotypes of HAV are present worldwide?
  25. HAV:
    Acute infxn?
    Chronic infxn?
    • Acute infxn= asymptomatic
    • Chronic infxn= no chronic infxn (rare cases in immunocompromised pts.)
    • Immunity:  Protective antibodies confer lifelong immunity
  26. HAV Vaccine
    Formalin inactivated ("killed" vaccine)

    *Live attenuated vaccine use in China
  27. Picornavirus family (including HAV): Genome
    • "Positive sense" genome (same as mRNA)
    • Translated as a polyprotein
  28. HAV genome (Picornaviruses):  Translation
    • Translated as a polyprotein in one single open reading frame
    • Proteolytically processed- ordered cleavages by viral proteases (proteases are "serine protease-like" cys proteases)
  29. "Serine protease like" cys proteases
    HAV proteases
  30. HAV Clinical Features:  Incubation period
    • Average= 30 days
    • Range= 15-50 days
  31. HAV Clinical Features:  Jaundice by age group
    • <6 yrs= <10%
    • 6-14 yrs= 40-50%
    • > 14 years 70-80%
  32. Rare complications of HAV
    • Fulimant Hepatitis
    • Cholestatic Hepatitis
    • Relapsing Hepatitis (10-15%)
  33. HAV Diagnosis:  Clinical
    • Discrete onset of symptoms
    •          Fatigue, abdominal pain, loss of    appetite, intermittnet nausea, vomiting
    •          Jaundice (mainly in adults)
  34. HAV Diagnosis:  Labs
    • Elevated IgM antibody to hepatitis A virus (anti-HAV) positive
    • Elevated serum aminotransferase (ALT/AST) levels0
  35. HAV is most common in what race in the US?
    American Indian or Alaskan Native
  36. HAV is most common in what parts of the world?
    Developing countries
  37. People who should get HAV vaccinations
    • Travelers to developing countries
    • MSM
    • IVDU
    • Outbreaks
    • High prevalence regions/populations
    • Persons w/ chronic liver disease or clotting disorders
  38. Can the HAV vaccine be used for post-exposure prophylaxis?
    Yes (<14 days)

    HAV vaccine is usually used to prevent further transmission, not to diminish symptoms
  39. HEV:  ss or ds; DNA or RNA
  40. Major source of epidemic hepatitis in the developing world
  41. Detection of this virus in the feces of swine, wildlife in endemic areas suggest that it may be a zoonotic virus.
  42. HEV Genome Structure:  ORF proteins and what they code for
    • ORF 1: Polyprotein
    • ORF 2: coat
    • ORF 3
  43. HEV:  Family? Genus?
    • Family= Hepeviridae
    • Genus= Hepevirus
  44. HEV has 4
    genotypes (1,2= humans only; 3,4= humans, swine, etc)
  45. Even though HEV has 4 genotypes, there is only a single
    serotype worldwide
  46. 5' end is capped (like mRNA)
  47. HEV Protease
    Papain-like (not cys protease, as most RNA viruses)
  48. Proteases:
    • HAV= Cys like (serine-protease)
    • HEV= Papain-like
  49. HEV Clinical Features:  Incubation period
    • Average 40 days
    • Range 15-60 days
  50. Case fatality rate of HEV
    • Overall: 1-3%
    • Pregnant women: 15-25%
  51. HEV Clinical Features:  Illness severity increases with
    higher age, chronic liver disease, pregnancy
  52. HEV outbreaks associated with?
    Contaminated drinking water (minimal person-to-person transmission)
  53. HEV:  Prevention and Control for travelers
    • Avoid drinking water/ice of unknown purity, uncooked shellfish, uncooked fruit/vegetables not peeled or prepared by traveler
    • Purified Ig from convalescent pts. (may or may not prevent infxn)
  54. HEV Vaccine:
    Based on what ORF protein?
    • Orf 2- Coat protein
    • Recombination protein from bacteria (HEV 239)
    • Licensed for use in China (100% efficacy from 3 doses)

    US Army made a vaccine (95% efficacy for 3 doses, but no plans for commercialization)
  55. HBV:
    Contain cores
    Dane particles (icosahedral capsule)
  56. HBV:
    Lack cores
    S particles (in envelope of host membrane that surround the Dane particles)
  57. HBV:  ss or ds, DNA or RNA
    DNA -partially ds  (related to hepadnavirus, and orthohepadnavirus)
  58. HBV replication
    Replicates via an RNA intermediate (reverse transcriptase), but is NOT a retrovirus
  59. HBV Capsid:
    Icosahedral capsid (genome, RT, Cp)
  60. HBV envelope contains
    surface antigen
  61. HBV enveloped particle
    Dane particle
  62. How many HBV human genotypes?
    8 (genotypes are based on the ENTIRE genome; genotypes diverge by at least 8%)

    Primate and human strains are closely related, but HBV doesn't infect chimps and vice-versa
  63. HBV serotypes are based on what?
    Based on cross-reactivity with anti-HbsAg Ab
  64. How many HBV serotypes?
    4 (don't correlate well with the 8 genotypes)
  65. HBV:
    Genotype based on?
    Serotypes based on?
    • Genotype is based on sequence, based on entire genome.
    • Serotypes based on cross-reactivity of anti-HBsAg Ab
  66. HBV Genome and Virion Structure
    • Inner: 
    • HBV Genome, RT is in genome
    • Core Protein (surrounds genome)
    • Surface protein is in the envelope obtained from the host
  67. HBsAg location
    On surface of Dane and "S" particles
  68. Required for HBsAg virus entry
  69. 3 HBsAg functions
    • Required for virus entry
    • ALWAYS present when virus is replicating
    • Basis of HBV vaccine (expressed in yeast)
  70. Anti-HBsAg
    Neutralizaing, different serotypes arise from differences in HBsAg amino acid sequence
  71. 3 proteins of HBsAg
    • PreS1
    • PreS2
    • S orf
  72. 3 forms of HBsAg
    • Differ due to which translational start site is used
    • Long:  PreS1, PreS2, S orf (S1, L)
    • Middle: PreS2, S orf (S2, M)
    • Short:  S orf only (S, S)
  73. 3 functions of HBV Polymerase
    • Required for recruitment of pgRNA to core
    • Converts pgRNA to genomic DNA
    • Target for nucleos(t)ide analogues (RT inhibitors/ chain terminators)    
    •       Lamivudine (3TC- also used for HIV), nucleoside analogue, frequently see active site mutations (YMDD)
    •        Adefovir (HBV specific), nucleotide analogue, YMDD mutations and other mutations
  74. Converts pgRNA to genomic DNA in HBV
  75. Target for nucleos(t)ide analogues (RT inhibitors/ chain terminators)
    HBV Polymerase
  76. Target for HBV vaccine
  77. Nucleoside analogue
    Nucleotide analogue
    • side- Lamivudine
    • tide- Adefovir
  78. Interaction between the P and S genes of HBV
    P completely overlaps S

    • S changes affect P (and vice-versa)
    • Some lead to reduced Ab recognition of ABsAg "a" site
    •        Escape mutatns may not be recognized by Ab elicited by vaccine
  79. Indicates active viral replication and therefore high transmissibility
  80. HBeAg:
    Translated from?
    PreC Met
  81. HBeAg:  What part of infxn?
    Found early in the infxn
  82. Can be lost due to
    preC mutation or downregulation of PCp
  83. Anti-HBeAg is associated with what stage of infxn
    Resolution of infxn (But it's not neutralizing or protective)
  84. Translated from PreC Met
  85. Translated from C Met
  86. Hallmark of HBV infxn; seen in acute, chronic, and resolved HBV
    Anti-HBcAg  (IgM early, IgG later)

    *Not neutralizing or protective
  87. Functions of HBx protein
    • Weakly transforming in tissue cultures
    • Pleiotropic effects (many different pathways)
    •     Transcriptional transactivator, modulates intracellular signaling (increases kinase activity, intracellular Ca++) --> Liver cancer
  88. Positive during window period before HBV progresses from acute to chronic.

    *The earlierl yo acquire HBV, the more likely you are to have a chronic infxn (for example, children who acquire HBV at birth will likely progress to chronic disease)
  89. Extra-hepatic manifestations of HBV (rare)
    • Transient serum-sickness-like syndrome
    • Acute necrotizing vasculitis
    • Membranous glomerulonephritis
    • Papular acrodermatitis of childhood (Gianotti-Crosti Syndrome)
  90. HBV extrahepatic manifestation that precedes jaundice by up to 4 wks
    Transient-serum-sickness-like syndrome
  91. Remission of membranous glomerulonephritis is associated with
    clearance of HBeAg
  92. Lentil-sized flat erythromatous papular eruption on face, extremities that is an extrahepatic manifestation of HPV
    Papular Acrodermatitis of Childhood (Gianotti-Crosti Syndrome)
  93. Symptomatic HBV or Asymptomatic HBV:  Which one leads to increased risk of cirrhosis or liver cancer?
    Both lead to increased risks, but more men progress than women
  94. Patients infected with what form of HBV are more likely to have hepatitis?
    HBeAg-mutant viruses
  95. Patients with high initial _____ often become chronically infected
  96. HLA type consistently associated w/ clearance, protects against vertical transmission.
    HLA DR13
  97. HLA types associated w/ chronic HBV infxn (but also w/ clearance of HCV)
    HLA DRB 1*11, DRB1*12, DQB1*0301
  98. HLA types associated with non-response to HBsAg vaccine (and with susceptibility to chronic HCV)
    HLA DRB1*03, DRB1*07
  99. More likely to get hepatitis: men or women?
  100. Associated with integration of HBV genomic DNA
    HBV progression to liver cancer (this is a dead end for the virus.  It will no longer replicate, but it may up/down regulate important cellular processes)
  101. 2 things that influence HBV progression to liver cancer
    • Integration of HBV genomic DNA
    • Chronic "activation" of hepatocytes (e.g. HBx protein)
  102. HIV vs. HBV:  DNA Stage
    Yes (HIV= linear, HBV= circular)
  103. HIV vs. HBV:  RNA Stage
    • HIV= Yes (2 copies), capped and polyA
    • HBV= Yes (1 copy), capped and polyA
  104. HIV vs. HBV:  Integration into chromosome
    • HIV= required
    • HBV= dead end
  105. HIV vs. HBV: Reverse Transcriptase
    • HIV= Yes (RT, RNase H, Integrase)
    • HBV- Yes (RT, RNase H, TP)
  106. HIV vs. HBV:  Proteolytic processing
    • HIV= required
    • HBV= no
  107. HIV vs. HBV:  Capsid assembly
    • HIV: Plasma membrane
    • HBV: Cytoplasm
  108. HIV vs. HBV:  Budding
    • HIV= Plasma membrane
    • HBV= ER/GA
  109. HBsAg:
    • A= +
    • C= +
    • R= -
  110. Anti- HBc IgM:
    • A= +
    • C= -
    • R= -
  111. Anti-HBc IgG:
    • A= +
    • C= +
    • R= +
  112. Anti-HBs:
    • A= -
    • C= -
    • R= +
  113. HBV DNA:
    • A= +
    • C= +/-
    • R= -
  114. HBeAg:
    • A= +
    • C= +/-
    • R= -

    (Not 100% reliable as HBeAg can be lost due to mutation)
  115. Anti-HBe:
    • A= -
    • C= +/-
    • R= +
  116. HBV infected cells
    • Larger
    • More prominent nuclei
    • "Ground glass" appearance
  117. Cells with "ground glass" apperance
    Cells infected with HBV
  118. HBV Clinical Features:  Incubation Period
    • Average 60-90 days
    • Range 45-180 days

    • Compared to averages:
    • HAV= 30 days
    • HEV= 40 days
  119. Average incubation periods for Hepatitis viruses:
    • HAV= 30 days
    • HEV= 40 days
    • HBV= 60-90 days
  120. HBV Clinical Features:  Jaundice
    • < 5 yrs= < 10%
    • > 5 yrs= 30-50%
  121. HBV Modes of Transmission
    • Sexual
    • Parenteral
    • Perinatal (not a major source of infxn in US)
  122. Body fluids with high concentration of HBV
    • Blood
    • Serum
    • Wound exudates
  123. Body fluids with moderate concentrations of HBV
    • Semen
    • Vaginal fluid
    • Saliva
  124. 2 things that prevent perinatal transmission of HBV
    • HBIG and HBV vaccine at birth (reudces by 95%)
    • Limvudine/Zidovudine tx late in pregnancy
  125. Therapy for HBV:
    Enhances immune system function
    Reduces HBV replication directly (modules POL levels)
    Little effect on HBeAg- patients
    Generally used in combination with antivirals
    IFN-alpha (intron A)
  126. Therapy for HBV:
    Nucleoside analogue
    RT Inhibitor-chain terminator
  127. HBV Therapy:
    Nucleotide analogue
    RT inhibitor
  128. Requires HBV for particle assembly
  129. Why does HDV require HBV for particle assembly?
    HDV lacks surface proteins
  130. HDV viral DNA is replicated by enzymes that are normally DNA-dependent RNA polymerases
    Host Pol I and Pol II
  131. HDV replication location
    Nucleoplasm AND Nucleolus
  132. HDV genome maturation requires
    Self Cleavage (ribozyme= catalytic RNA)
  133. Two forms of Delta Ag
    • Long (L-HDAg): required for assembly
    • Short (S-HDAg): required for replication
  134. Expression of what form of Delta Ag is controlled by RNA editing (Ade deamination)
    Long (L-HDAg)
  135. From of Delta Ag required for assembly
  136. From of Delta Ag required for replication
  137. Transmission of HDV is same as HBV except
    HDV does not usually see perinatal transmission
  138. HDV coinfection with HBV:
    Acute disease?
    Chronic disease?
    • Acute disease= severe
    • Chronic disease= low risk

    HBV vaccine is protective
  139. HDV Superinfection on top of Chronic HBV
    • Usually develop chronic HDV infxn
    • High risk of high risk of severe chronic liver disease
    • HBV vaccine has no effect (Modify pt. behavior to prevent exposure)
  140. HDV Superinfection or Coinfection:  High risk of severe chronic liver disease
  141. HDV Superinfection vs. Coinfection:  HBV vaccine is protective
  142. HDV Superinfection vs. Coinfection: 
    Elevated ALT?
    • Coinfection
    • Superinfection
  143. HDV Superinfection vs. Coinfection Viral Markers:
    IGM anti-HBc+
  144. HDV Superinfection vs. Coinfection Viral Markers:
    IGM anti-HBc-
  145. HCV:
    • Family= Flaviviridae
    • Genus= hepacivirus
  146. HCV:  ss or ds, DNA or RNA
  147. Enzyme present in HCV
    RNA-dependent RNA Polymerase
  148. HCV is like the flu in that it has frequent mutations
    It has no "proofreading" -> HCV variants (quasispecies)
  149. HCV:  Orfs?
    • 1 ORF= Single Polyprotein
    •     Cleaved co- and post-translationally
    •     Requires both host and viral protease activity
  150. HCV is sensitive to what drug?

    (Also Boceprevir and Telaprevir)
  151. Ribavirin targets
    RNA-dependent RNA Polymerase of HCV
  152. HCV:  Replication location
    Replicates on surface of ER, buds into GA

    *Replication occurs in internal membranes/cytosolic membranes
  153. Form of hepatitis that doesn't grow in lab animals
    • HCV
    • (Delete E1 and E2 -> minigenome, which will replicate in HepG2
  154. HCV:  Cell rearrangement
    • Get whole cell rearrangements during the assembly and uncoating process
    • Neutralizing Abs can't neutralize the viruses, b/c the neutralizing epitope is only present at the point of fusion of capsid proteins.
  155. HCV and progression to liver cancer
    • HCV does NOT integrate into genome
    • May lead to liver cancer due to "chronic activation" of hepatocytes
  156. HCV protein implicated in several transforming pathways, one of which may lead to liver cancer
    Core Protein (C)
  157. HCV genotypes
    6 major ones
  158. HCV genotypes have what % of sequence identity

    Genotype allows us to predict tx outcome (IFN is less effective against genotype 1)
  159. Multiple quasispecies within a single person due to
    High error rate of RNA-dependent RNA polymerase in HCV
  160. HCV Clinical Features:
    Incubation period
    • Average= 6-7 wks
    • Range 2-26 wks
  161. ALT spike followed by anti-HCV ab
    Acute HCV w/ recovery
  162. ALT spike and continued fluctuation
    anti-HCV Ab increases
    HCV w/ progression to chronic infxn
  163. Is anti-HCV Ab protective?
    Anti-HCV Ab is an Ab against the capsid, but is not protective
  164. Chronic HCV Progression Times:
    Clinically significant chronic hepatitis
    Hepatocellular CA
    • CSCH =~10 years
    • Cirrhosis= ~21 years
    • HCC= ~29 years
  165. 6 Extrahepatic manifestations of HCV
    • Hypergammaglobulinemia
    • Glomerulonephritis
    • Cryoglobulinemia
    • Porphyria cutanea tarda
    • Lichen planus
    • Association w/ Type 2 DM
  166. HCV Tests:
    Initial diagnosis, screening test
    Anti-HCV ELISA
  167. HCV Tests:
    Confirms ELISA results
  168. HCV Tests:
    Confirms HCV infxn
    HCV PCR qualitative
  169. HCV Tests:
    Assesses viral load
    HCV PCR quantitative
  170. HCV Tests:
    Predicts IFN responsiveness
  171. 4 things NOT associated with disease progression in HCV infected patients
    • HCV "viral load"
    • HCV genotype
    • Serum ALT
    • Smoking
  172. Most common cause of HCV infxn in US
    Injecting drug use
  173. Mother-to-infant transmission of HCV
    • Post-exposure prophylaxis NOT available
    • No need to avoid pregnancy or breastfeeding (no reliable evidence of transplacental transmission)
    • *Consider bottle feeding if nipples are cracked/bleeding
  174. How should an HCV + mother deliver her child
    No need to choose mode of deliver based on HCV infxn, but test all children born to HCV+ woman
  175. Unexpected risk factor for HCV transmissino
    Sharing devices for crack or cocaine inhalation
  176. HCV and HIV
    Increased HCV viremia w/ HIV
  177. Preventing HCV infxn
    • No HCV Vaccine
    • Anti-HCV Ig from pts. not protective
  178. HCV Tx options
    •  (Peg) IFN-a-2b + ribaviring
    •         Peg decreases IFN turnover
    • Protease Inhibitors (Boceprevir and Telaprevir)
    •       Triple therapy w/ IFN/Rib now considered standard of care for genotype I
  179. HCV genotype less responsive to IFN
    Genotype 1
  180. Does triple therapy tx of HCV cure pt?
    No, but it makes them a sustained responder (where HCV RNA levels are undetectable)
  181. HCV in Liver Transplans
    • Pts. w/ decompensated liver disease should be considered
    • Recurrence of HCV infxn >90% in liver grafts
    • Level of viremia increases dramatically w/ post-transplant immunosuppression
    • Pt. and graft survival rates are good in short term
  182. Test:  IGM anti-HAV
    Acute HAV
  183. Test: IgM anti-HBcAg
    Acute HBV
  184. Test:  HBsAg
    Acute or chronic hepatitis B
  185. Test:  Anti-HCV
    Acute or chronic hepatitis C
  186. Test:  HBsAg
    Acute or chronic HBV
  187. Test: Anti-HBc
    Acute or chronic hepatitis B
  188. Test:  Anti-HCV
    Acute or chronic HCV