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97 Cards in this Set

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Hepatitis A (epidemiology)
Enteric (fecal-oral)
Heptatis A (virus type)
picornavirus
Hepatitis A (immunity)
passive--> active in places with low sanitary conditions

(In developing countries, nearly everyone is seropositive by age 5)
Hepatitis A (populations affected)
over disease is rare in developing countries, due to:
active --> passive immunity

and the fact that childhood infections are often anicteric (w/o jaundice)

under high sanitary conditions susceptibles accumulate in the older age groups
Hepatitis A (incubation period)
~30 days
Hepatitis A (pathophysiology)
fecal excretion of virus (several weeks)
and viremia (for about a week) precede symptomatic disease

viremia serves to infect liver, viral growth in liver results in anorexia, nausea, fever, followed by jaundice and elevated LFTs
LIVER FUNCTION TESTS
(LFTs)

values elevated in Hepatitis A

example is AST- enzyme released by destruction of hepatic cells
Hepatitis A (mechanism of hepatocyte damage)
lysis of infected cells to release progeny virions
effects of inhibited biliary excretion of conjugated bilirubin seen in viral hepatitis
JAUNDICE (from bilirubin in tissues)
DARK URINE (bilirubin glucuronide?)
PALE FECES (bilirubin metabolites)
AST levels in Hepatitis A vs. Hep B
(an LFT)
HEP A:
elevated from +1 to +2 months post infection
(peak +1.5 months ~400)

HEP B:
elevated from ~+2 --> +5 months
(peak ~350 @ +4 months)
Hepatitis A (types of focal epidemics)
a) H2O-borne (esp. in summer camps)
b) from raw/undercooked shellfish- contaminated by sewage
c) within one family (spread by children's fecal contamination)
d) from an infected food handler in the USA
e) from fecally contaminated food, usually imported
Hepatitis A (transmission)
in addition to enteric spread can be transmitted by blood (as describe for Hepatitis B)
Hepatitis A (prevention)
Passively transferred (intramuscular injection) pooled human gamma globulin: gives good protection

Now that vaccine is available, passive immunization used primarily after possible exposure to Hep A virus

Passive immunity from pooled gamma globulin:
a. Prevents jaundice and malaise after infection with HAV, but:
b. Elevated LFTs show some virus-induced damage. Solid immunity results from this modified disease (example of passive --> active immunity)

c. pooled normal human gamma globulin provides protection for ~4 months
Hepatitis A (vaccine)
a formaldehyde killed vaccine

has replaced passive immunization in most instances

recommended for all children, for travelers to highly endemic areas
men who have sex with men
persons who regularly receive blood products
adults who live in states with history of elevated rates of infection and persons who have chronic liver disease of any kind
Hepatitis A (diagnosis)
virus can be cultured in the laboratory, but not generally available.

There is a reliable serological test for Ab to HAV.
Interpret serologic test for Hepatitis A in a jaundiced patient:

Anti-HAV-IgG:(-)
Anti-HAV-IgM:(-)
current disease is not HepA. The patient never had HepA or the vaccine
Interpret serologic test for Hepatitis A in a jaundiced patient:

Anti-HAV-IgG:(+)
Anti-HAV-IgM:(-)
current disease is not HepA

patient was infected with hepA virus sometime in the past or received the vaccine sometime in the past
Interpret serologic test for Hepatitis A in a jaundiced patient:

Anti-HAV-IgG:(+)
Anti-HAV-IgM:(+)
acute infection with hep A virus (or a recent infection within previous 4 months)

or recent vaccine (easily ruled out by medical history)
Why might the combination of IgM(+) and IgG (-) not be seen in serologic test for HAV?
IgG response begins before the patient becomes symptomatic, whereas IgM response does not begin until later and also does not last as long
How have non-endemic areas (such as the US) controlled HAV
public health measures (good sweage and sanitation)
Hepatitis A (increased risk behavior)
sexual behavior that includes direct or indrect oral/anal contact
How to study an outbreak of disease:
a. first be sure that it is an epidemic and not simply more efficient discovery of cases of a disease endemic in the community

b. Then, orient the epidemic in terms of place, person and time.
1. PLACE: plot geographically (does clusterin suggest some pattern of transmission)
2. PERSON: tabulate the cases with respect to occupation, age, specific food consumption, etc... Does the resulting pattern suggest a mode of exposure?
3. Time: Plot the appearance of new cases as a function of time.
INCIDENCE: # of new cases and
PREVALENCE: total # of cases
INCIDENCE
# of new cases
PREVALENCE
total # of cases
COMMON-SOURCE EPIDEMIC
simplest epidemic, in which:
-all individuals are infected at rougly the same time
-new cases are clustered around the incubation period

(bell curve, with the peak incidence (y axis) @ time of average incubation period (time= x axis)
Hepatitis B (virus type)
hepadnavirus
Hepadnavirus (nucleic acid)
circular DNA (mostly double stranded, but has single stranded regions)

virion contains an enzyme for replication of its genome (a reverse transcriptase, erroneously called polymerase)
Hepadnavirus (virion structure)
lipoprotein envelope (w/ viral glycoproteins as outer later)

symmetry ~ related to ICOSAHEDRAL

circular DNA (mostly double stranded)

virion contains enzyme to replicate genome (reverse transcriptase!)
Hepatitis B Particles
infectious virion (includes HBsAg, HBcAg, DNA, DNA Pol, HBeAG??)

antigenic, but not infectious fragments of HBV (HBsAg sphere and HBsAg filamen)
Hepatitis B (incubation period)
~70 days (range 50-180 days)

relatively long, (relative to Hep A ~30 Days)
Hepatitis B (onset)
insidious

(WHAT AB HEP A?)
Hepatitis B (modes of transmission)
a. intentional or careless parenteral transfer of blood or blood products

b. sexual transmission

c. perinatal infection of neonates by their mothers. these infections are more likely to result chronic disease and primary liver carcinoma
Hepatitis B (diagnosis)
serological tests for presence of the Hep B virus and Ab to Hep B

HB-Ags = Hepatitis B antigens, mixture of virions and sub-viral particles
HB-Ags
two groups:
core (nucleocapsid) antigens
and
surface (envelope glycoprotein) antigens
core antigen HBeAG
strongly correlates with the presence of infectious HBV and (in chronically infected patients) with progression to hepatic carcinoma
populations that are/have had high incidence of Hep B
drug addicts who share needles
male homosexuals (sexual transmission, has been substantially reduced with vaccine and safe-sex)
Hepatitis B (mechanism of hepatocyte damage)
primarily immunologically mediated

cytotoxic T-cells recognize HBV peptides presented by MHC-I on the cell surface
presence of HB-Ag in serum
usually seen in serum for several weeks after infection

~5% of infections result in chronic disease in which HB-Ag persists for years or for life (associated with chronic hepatitis and primary liver carcinoma)

chronic carriers of HB-Ag are an infectious hazard to others

presence of circulating core antigen "e" HBeAg is correlated with the presence of infectious HBV
HBeAG
circulating core antigen "e"

presence correlates with the presence of infectious HBV
Perinatal transmission of Hepatitis B virus
transmission of Hep B from HB-Ag-positive mothers to neonate will result in 90% of children becoming chronic HBV carriers.

25% of these carriers will die of liver carinoma or chronic hepatitis

incidence of neonatal infection can be reduced with a combination of passive immunization with HB-immune globulin and an active immunization with HB-vaccine given immediately after birth

routine screening of all pregnant women is used to id neonates at risk and thus requiring immunization
original method for making inactivated viral vaccines
virions purified, then infetivity inactivated with a chemical such as formaldehyde (ex: inactivated polio vaccine)
modern equivalent of inactivated vaccine
purified virions are disrupted and the antigens that ellicit neutralizing Abs are purified and used as the vaccine

chemical inactivation may be used to eliminate any residual life virus

alternatively, viral genes that encode the neutralizing antigens can be cloned and expressed in some suitable microbe (such as yeast)

**these two modern vaccines are called subunit vaccines
SUBUNIT VACCINES
contain only the antigenically important subunit of the virion (still considered killed vaccines bc no infectious virions are present)
DNA-VACCINES:
a short DNA segment encoding the desired viral antigen is expressed intracellularly in the patient vacccinated with the DNA. the resulting protein stimulates both cellular and humoral immunity
Other potential future vaccines
viral antigens expressed in edible plants through genetic engineering
Immunization against Hepatitis B
1. Passive immunization with pooled human IgG prepared from the serum of persons previously show to have large amts of Ab against HBV (unlike HAV where normal gamma globulin works)
original Hep B vaccine
produced by chemical inactivation of HBsAg purified from human serum
current US vaccination used to prevent HBV
genetically engineered:
viral genes for HB envelope glycoprotein antigens are expressed in yeast

this vaccine is not live

strongly recommended for high risk groups (hospital personnel, particularly those that come in contact with patients' blood)
immunization strategy for infants borne to HB-Ag positive moms
neonates given both anti-HB-immunoglobulin AND the vaccine
CDC recommendation re: HBV vaccinations
since most infections take place after puberty (bc HBV is an STD) the CDC recomends universal childhood immunization to eliminate this disease
Post-Transfusion hepatitis has been markedly reduced by...
eliminating as donors:
a. former hepatitis patients
b. people who have lived with hepatitis patients in the past 6 months
c. people who have had a transfusion in the past 6 months
d. people whose serum is positive for HB-Ag (a critical parameter in the prevention of viral infection by blood transfusion is the *Window period (interval between time that a donor can transmit a given disease and the time that that donor's infection can be detected by a given test done with the donated blood
window period
interval between time that a donor can transmit a given disease and the time that that donor's infection can be detected by a given test done with the donated blood

generall longer when a serological test is used than when a PCR-based test is used

PCR-based assays for HBV and HCV will eliminate most of the post-transfusion hepatitis (problem of post-transfusion hepatitis due to other viruses remains)
effect of using volunteer donors on risk of post-transfusion hepatitis
risk markedly reduced
Hepatitis C (virus type)
Flavavirus
most nonA-nonB hepatitis is caused by what?
Hepatitis C virus (HCV)
an enveloped
+ stranded
RNA virus
HCV diagnosis
serological test for anti-HCV

has been replaced with a PCR test for HCV RNA ** most reliable method
HCV transmission
blood transfusion, needle sharing, others are inconclusive
what causes liver damange in HCV?
like hepatitis B, hepatocyte damage in acute and chronic hepatitis C is immunologically mediated
HCV incubation period
long, ~60 days
Long term prognosis for those infected with HCV
most people do not eradicate HCV upon recovery from acute (or asymptomatic primary infection).

they remain asymptomatic for 10 to 20 years

but up to 20% will develop life-threatening cirrosis and a smaller @ with develop generally fatal hepatocellular carcinoma
How common is chronic hepatitis in the US? What is the fatality rate?
In the US 4 million chronically infected (4x # of HIV infections)
late manifestations of chronic infection cause 10,000 deaths per year
What do Hep B and C have in common?
-long incubation period
-Both cause acute and chronic disease, (but relatively uncommon (<5%) in B and relatively common (~75%) in C)
-chronic hepatitis B and C are both substantial risk factors for primary liver cancer
-prodromal symptoms of arthritis and rash in some acute infections (non specific symptoms pre-jaundice)
-hep B is transmitted perinatally and as an STD (hep C probably does too)
Treatment of Chronic Viral Hepatitis
chronic hepatitis caused by HBV and HCV can be treated with:
-prolonged (4-6 months) treatment with alpha interferon

-treatment is expensive and has relatively low rate of success

chronic hep caused by HBV can also be treated with lamivudine (a chain terminating reverse transcriptase inhibitor) originally used to treat AIDS

chronic hep caused by HCV responds better to interferon + ribavirin
lamivudine
used as treatment for chronic hepatitis cased by HBV

chain terminating reverse transcriptase inhibitor (further evidence that the reverse transcriptase in HBV virion plays an essential role in replication)

originally used to treat AIDS
Hepatitis D (virus type)
defective RNA virus
Hepatitis D (nucleic acid)
circular minus-stranded RNA genome
Hepatitis D (replication)
can produce infectious progeny only in cells also infected by hepatitis B virus
Hepatitis D affects what population?
those infected with acute or chronic Hep B (because Hep D genome does not encode its own glycoproteins, has to be coated with Hep B envelope)
What happens if a Liver cell is infected by a Hep D virion?
Hepatitis D RNA multiples, but no virions are produced and not enough cells are damaged to produce disease
What happens if a Liver cell is infected by Hep B virion
Hepatitis B virions are produced and disease results from immune response to infected hepatocytes
What happens if a Liver cell is infected by:
HEPATITIS B VIRIONS
and
HEPATITIS D VIRIONS
Both Hepatitis B virions
and
Hepatitis D virions are produced and disease results from a severe immune response to infected hepatocytes
How is Hepatitis D diagnosed?
cells infected with Hep D virus produce one protein unique to hep D.

patients make an immune response to this protein allowing a serological diagnosis
Hepatitis D onset
often acute
sometimes severe and life threatening
Mechanism by whihc HDV amplifies pathogenesis of hep B
is unknown
Hepatitis E (virus type)
calcivirus
Hepatitis E (virion stucture)
naked
+ stranded RNA
Hepatitis E (etymology)
fecal-oral pathway
Where is hepatitis E most common?
in developing countries where the mortality rate is particularly high in pregnant women (~20%)
HAV (virus type)
Hepatitis A Virus (a picornavirus)
anti-HAV
antibody to hepatitis A virus
HBV
Hepatitis B Virus
enveleoped virus of the hepadnavirus type "Dane particle"
What is HBsAg?

Where is it found?
Hepatitis B surface (envelope glycoprotein) antigens

Found on the surface of the virion and on the spherical and tubular subviral particles
What is HBcAg
Hep B core (nucleocapsid) antigens
What is HBeAg?

Why is it significant?
Hepatitis B "e" antigen.

presence of this antigen is a surrogate marker for viral replication

strongly correlated with:
-the presence of infectious hep B virions
and
- (in chronically infected patients) strongly correlated with progression to hepatic carcinoma
what is anti-HBs
Antibody to hepatitis B surface antigen (Ab to envelop glycoprotein)
What is anti-HBc
Antibody to hepatitis B core antigen (nucleocapsid)
What is anti-HBe
Antibody to hepatitis B e antigen
route of infection in HAV
fecal-oral
route of infection in HBV
blood transfer, venereal, perinatal
route of infection in HCV
blood transfer (venereal? perinatal?)
route of infection in HDV
blood transfer and venereal (perinatal?)
requires co-infection with HBV
route of infection in HEV
fecal-oral
EB Virus (virus type)
herpes virus
EB Virus (transmission)
saliva transfer
What do hep A and E have in common?
fecal-oral enteric pathogens
acute disase only
incubation (~30days) is relatively short (compared to other hepatitis viruses)
What do hep B, C, and D have in common?
-transferred by blood and blood products
-venereally (C?) and perinatally (C?D?) transmitted
-can cause chronic disease with liver damage
-relatively long (50-70 days) incubation period among hepatitis viruses
which viruses can cause hepatocellular carcinoma?
Chronic B and C infection