sbm2044 hepatitis

							Hepatitis
19 Muharram 1428
 7th February 2007
    SBM 2044
   http://www.sumanasinc.com/webcontent/anis
    amples/microbiology/herpessimplex.html
Hepatitis
   Hepatitis is an inflammation of liver
   It is usually caused by viral infections, toxic
    agents or drugs but may be an autoimmune
    response.
   It is characterised by jaundice, abdominal
    pain, liver enlargement and sometimes fever.
   It may be mild, or can be acute leading to
    fulminant hepatitis. Others, usually viral or
    alcoholic are chronic, and can lead to
    cirrhosis and liver cancer.
Characteristics of hepatitis
viruses
Virus          Hep A      Hep B       Hep C Hep D     Hep E

Family         Picorna Hepadna Flavi- UC              UC
               -viridae -viridae viridae
Envelope -                +           +       +       -
                          (HBsAg)             (HBsAg)
Genome         ssRNA          dsRNA   ssRNA   ssRNA   ssRNA
Transmission      F            P          P      P        F

    • F = faecal-oral route
    • P = parenteral
Hepatitis A virus (HAV)
   Hep A virus
   Picornaviridae; linear ss RNA; size 7.5 kb
   Only one serotype, no antigenic cross-reactivity with
    HBV etc
   Stable in 20% ether, acid pH1 for 2h, 60°C for 1h.
   Destroyed by autoclaving 121°C for 20mins, boiling
    water 5 mins, dry heat 180°C for 1h, UV radiation,
    chlorine, formalin.
   Heating food >85°C for 1min or disinfecting
    surfaces with sodium hypochlorite inactivate HAV.
   HAV is detected in stool.
Hepatitis A
   Faecal-oral route.
   Spread in families, institutions, day care
    centers, neonatal intesive care units and
    among military troops.
   An indication of poor sanitation and poor
    personal hygiene.
Identification
   HAV – in stool and liver preparations
   Immune EM
   Measure Ab in serum
   PCR
   Tissue culture – no cytopathic effects are
    apparent.
   Most cases will have complete recovery.
Hepatitis B virus (HBV)
   Hepadnavirus
   HBV establishes chronic infections esp in infants
    and a major factor of eventual hepatocellular
    carcinoma.
   HBsAg – stability does not always conincide with
    that of the infectious agent. Both are stable at -20°C
    for over 20 yrs and stable to repeated freezing and
    thawing.
   HBV but not HBsAg is sensitive to 100°C for 1 min
    or 60°C for 10hrs. HBsAg is stable at pH2.4 for
    <6hr.
   HBsAg is not destroyed by UB irradiation of plasma
    or other blood products.
Hepatitis B
   Other viruses, such as Yellow Fever, Epstein- Barr
    (EBV) and cytomegalovirus (CMV) as well as
    parasites and bacteria, can cause hepatitis as a
    secondary effect.
   HBV is worldwide in distribution.
   HBsAg can be detected in saliva, nasopharyngeal
    washings, semen.
   Health care personnel (medical/dental surgeons,
    nurses, physicians) have higher risk and prevalence
    of detectable HBsAg or anti-HBs than those who
    have no occupational exposure to patients or blood
    products. They become apparently healthy HBsAg
    carriers.
Hepatitis B virus
Hep B Antigens
    Hepatitis B DNA (HBV DNA)
    Immediate detection in bloodstream after initial infection ~1 week
     after infection. It maybe that the level of HBV DNA may indicate
     how fast the virus is replicating – using very sensitive and
     expensive PCR. It is generally only used research purposes,
     however in can be used to confirm the presence of hepatitis B
     and or measure viral load for viral mutants that do not produce
     the "e" and/or normal surface antigens.
    Hepatitis B DNA polymerase. (HBV DNA Polymerase, DNAp)
    This enzyme can be detected in the bloodstream soon after initial
     infection by HBV at about the same time as HBV DNA ~ 1 week.
     Tests generally only used as indicators of disease progression,
     suitability for therapy and research purposes.
Hep B Antigens
   Hepatitis B Core protein. (HBcAg)
   Not detectable in the bloodstream, however it can be detected in the
    sample of liver cells taken after a liver biopsy. Generally the HBc
    proteins link together to form the hepatitis B core that encapsulate
    HBV DNA and DNA Polymerase.
   Hepatitis B Surface protein(s). (HBsAg)
   Outer surface coat composed of hepatitis B surface proteins is
    produced in larger quantities than required for the virus to
    reproduce. In some cases these particles encapsulate a core
    particle and produce a complete, and infectious, virus particle that
    enters the blood stream and can infect other liver cells. It does
    however take a while for these proteins to appear ~1 to 6 weeks
    before symptoms occur HBsAg appears. A positive test for the
    presence of hepatitis B surface protein (HBsAg), is the standard
    currently taken to indicate current infection with hepatitis B. If HBsAg
    is present for more than 6 months this is generally taken to indicate
    chronic infection. Majority of chronic HBV individuals are
    asymptomatic; may or may not have biochemical and histological
    evidence of liver disease. Chronic carriers are at high risk of
    hepatocellular carcinoma.
Hep B Antigens
   HBe Protein. (HBeAg or 'e' antigen)
   The Hepatitis 'e' antigen (HBeAg) is a peptide and representing the
    viraemic stage of hepatitis B virus, this in turn leads to the person being
    much more infectious and at a greater risk of progression to liver
    disease. The exact function of this non-structural protein is unknown,
    however it is thought that HBe may be influential in suppressing the
    immune systems response to HBV infection(?). HBeAg is generally
    detectable at the same time as HBsAg and disappears before HBsAg
    disappears. The presence of HBeAg in chronic infection is generally
    taken to indicate that HBV is actively reproducing and there is a higher
    probability of liver damage. In acute infection HBeAg is generally only
    transiently present.
   However mutant strains of HBV exist that replicate without producing
    HBeAg.
   In many cases infection with these mutant strains is more aggressive
    than HBe producing strains(?).
   The presence of HBeAb is generally taken to be a good sign and
    indicates a favorable prognosis.
HBV vs Human
   Majority of people will recover from Hepatitis B and around half of these
    are asymptomatic. Recovery means that no HBsAg is found in the
    blood and the Hepatitis B Antibody (HBsAb) is present. HBsAb
    usually persists for life after recovery.
   These are generally the last antibodies to appear. HBsAb can
    neutralise the hepatitis B virus and there appearance taken as an
    indicator that an initial infection has been defeated.

   Antibodies to HBc (HBcAb, Anti-HBc).
   The first detectable antibody to appear around 8 weeks after infection
    with HBV are antibodies to the HBV core protein. The initial antibodies
    are of class IgM and IgG and generally appear after the appearance of
    HBsAg but often before ALT elevations. These antibodies to HBcAg do
    not neutralise the virus. HBcAb's persist in serum after an infection with
    HBV and these are predominantly of type IgG. The presence of a
    strong IgM HBcAb's is indicative of acute phase infection. The presence
    of IgG HBcAb's with no IgM HBcAb's antibody may be present in
    chronic and resolved cases of hepatitis B infection, this has been used
    to determine if the presence of HBsAb's was due to vaccination or by
    previous exposure to the live virus.
Detecting HBV
   ALT alanine aminotransferase and AST (aspartate
    aminotransferase).
   ALT and AST are enzymes produced in liver cells that can be
    detected in the blood stream. The normal range for ALT is
    between 0-40. When liver cells are damaged these enzymes are
    released and elevated levels are detected in serum. The value of
    ALT in the blood stream is generally taken to be an indicator of
    the damage that hepatitis causing to liver cells. However damage
    may be occurring with little or no elevation of ALT (this is
    especially true for hepatitis C and people with end stage liver
    disease).
   ALT and AST and other substances are measured when a liver
    function test. However other drugs and especially alcohol can
    elevate these readings artificially.
Pathology
   Acute hep B is characterised by spradically
    abnormal aminotransferase values and
    hepatomegaly.
   Histologically, lobular architecture is
    preserved, portal inflammation and pale
    hepatocytes (cobblestone arrangement); and
    slight to absent fibrosis.
   Chronic viral hepatitis type B frequently leads
    to a macronodular cirrhosis in non-allografted
    livers.
   Hepatitis B
Hepatitis C virus
   A positive-strand RNA virus; from family
    Flaviviridae
   Hepatitis C is usually clinically mild, with
    minimal to moderate elevation of liver
    enzymes.
   Despite the mild disease, 70-90% of cases
    progress to chronic liver disease.
   Diseases in chronic HCV infections inc mixed
    cryoglobulinaemia and glomerulonephritis.
Hepatitis D virus
   HDV infects all age groups – ppl with multiple
    transfusions, IV drug users, and their close contacts
    are at high risk.
   HDV can be transmitted in a similar ways as HBV
    (though not sexually), and perinatally.
   Infection is HBV-dependent, as HBV provides an
    HBsAg envelope for HDV. In some HBV infections,
    delta-Ag (HDAg) and anti-delta were detected. In
    blood, HCV contains HDAg surrounded by an
    HBsAg envelope.
   Genome of HDV consists ss circular and negative-
    sense RNA; 1.7kbp (smallest).
Hepatitis E virus
   Transmitted enterically; epidemic in
    developing countries where water supplies
    are sometimes faecally contaminated.
   Viral genome is positive-sense ss RNA; 7.6
    kbp in size.
Clinical findings
   Not possible to make clinical distinction
    among cases caused by the hepatitis viruses.
   Hepatitis may occur as complication of
    leptospirosis, syphilis, tuberculosis, all of
    which can be treated with drug therapy.
Treatment
   Treatment of patients with hepatitis is supportive
    and allowing hepatocellular damage to resolve and
    repair itself.
   Only HBV and HCV have specific treatments.
   Recombinant interferon-α, lamivudine (reverse
    transcriptase inhibitor) reduces HBV DNA levels.
   Orthotopic liver transplantation for chronic hepatitis
    B and C end-stage liver damage. However risk of
    reinfection on graft is at least 80% with HBV and
    50% with HCV.
Prevention and Control
   1. Standard precautions when handling blood, body fluids and
    materials contaminated with hepatitis viruses – gloves, masks
    and eye protection, discard needles.
   2. HAV – formalin-inactivated HAV vaccines and reasonable
    hygiene.
   3. HBV - provides protection against infection with HBV by
    producing immunity or antibodies to the surface protein or outer
    coat of the virus, HBsAg. The first vaccine was produced by
    purifying this surface protein from the plasma of chronically
    infected persons. Subsequently, this surface protein was
    produced in yeast by recombinant DNA technology. However,
    plasma-derived vaccines continue to be used widely throughout
    the world.
   4. HCV – no vaccine.
Picornaviruses
     19 Muharram 1428
      7th February 2007
         SBM 2044
Picornaviruses
   PicoRNAvirus = small RNA virus
   Include 2 main groups:
   Enteroviruses – transient inhabitants of human
    alimentary tract, may be isolated from throat or
    lower intestine.
   Rhinoviruses – isolated chiefly from nose and throat.
   Cause diseases ranging from severe paralysis to
    aseptic meningitis, myocarditis. The most serious
    disease by enterovirus is poliomyelitis.
   Picornaviruses replication occurs in cytoplasm.
Properties and Classification
   Genome: ss RNA, linear, + sense, size is
    7.2kb (human Rhinovirus) to 8.4kb
    (Aphthovirus).
   No envelope, consists of 4 major
    polypeptides (surface VP1 and VP3 for Ab-
    binding sites; and internal VP4 is associated
    with viral RNA).
   Enteroviruses are stable at acid pH (3-5) up
    to 3hr, whereas rhinoviruses are acid-labile.
I. Enterovirus Group
   Poliomyelitis – acute infectious disease that
    affects the central nervous system.
    Destruction of motor neurons in spinal cord
    results in flaccid paralysis. Most infections
    are subclinical.
Pathogenesis and Pathology
   Mouth is the portal entry of the virus, primary
    multiplication in oropharynx or intestine.
   Virus is regularly present in throat and in the
    stools even before the onset of illness, or for
    many weeks even with a high Ab levels in
    blood.
   It is believed that the virus multiplies in
    tonsils, LN of neck, Peyer’s patches, and
    circulating in the blood to infect CNS.
Clinical Findings
   Abortive poliomyelitis – mild form of illness with
    fever, malaise, drowsiness, headache. Recovery in
    a few days.
   Nonparalytic poliomyelitis (aseptic meningitis) –
    symptoms as above plus stiffness and pain in the
    back and neck; last 2-10 days.
   Paralytic poliomyelitis – flaccid paralysis from
    lower motor neuron damage. Recovery within
    6mths.
   Progressive postpoliomyelitis muscle atrophy –
    reappearance of paralysis and muscle wasting
    decades after their paralytic poliomyelitis, a result of
    physiologic and aging changes in patients burdened
    by loss of neuromuscular functions.
Diagnosis
   Virus recovered from throat swabs taken
    soon after onset of illness, stool samples.
    Uncommonly from the cerebrospinal fluid.
   Identified by neutralisation with specific
    antiserum.
Prevention and Control

   Periodic booster to maintain immunity.
   Formalinised vaccine (Salk) is killed-virus
    vaccine, which induces humoral Abs but not
    local intestinal immunity so virus is still able
    to multiply in the gut.
   Oral vaccines contain live attenuated virus
    (Sabin). This vaccine produces IgM, IgG and
    also secretory IgA Abs in intestine.
Coxsackieviruses
   Produce diseases in humans such as:
    herpangina, hand-foot-and-mouth disease,
    acute haermorrhagic conjunctivitis by type A;
    and epidemic myalgia, myocarditis,
    pericarditis and generalised diseases in
    infants by type B.
   Monkeys are mostly susceptible.
Echoviruses
   Echoviruses = enteric cytopathogenic human
    orphan viruses.
   Viruses may be recovered from throat and
    stools, similar to that of other enteroviruses.
   Associated diseases are aseptic meningitis,
    rashes (“Boston exanthem disease”) which
    are common in young children, muscle
    weakness and spasm.
II. Rhinovirus Group
   Are common cold viruses, cause upper resp T
    infections.
   Can be found in nasal secretions within 2-4 days
    after exposure. Direct correlations between amount
    of virus and severity of illness.
   Replication is limited to surface epithelium of nasal
    mucosa.
   Immunity: Neutralising Ab develops in serum and
    secretions of most persons. Interferon may play a
    role in recorery – a 5-day course of intranasal IFN-α
    is an effective prevention within a family.
Foot-and-mouth Disease
   Aphthovirus of Cattle
   The disease in animals is highly contagious
    in the early stages of infection when viraemia
    is present when vesicles in the mouth and on
    the feet rupture and liberate large amount of
    virus. Excreted materials remain infectious for
    long periods.
   Formalin-treated vaccines do not produce
    long-lasting immunity.
Reoviruses &
 Rotaviruses
    19 Muharram 1428
     7th February 2007
        SBM 2044
General properties
   Common disease is acute gastroenteritis.
   Ds RNA, linear, icosahedral with double capsid
    shell.
   No envelope, have 9 structural proteins with core
    contains several enzymes.
   Reoviruses are usually stable to heat, pH 3-9 and to
    lipid solvents.
   Replications occur in cytoplasm
   Rotaviruses are major cause of infantile diarrhoea.
   Reoviruses are good models for molecular studies
    of viral pathogenesis.
Reovirus Replication
   Receptors are viral haemagglutinin (α1 protein), a minor
    component of outer capsid.
   After attachment and penetration, uncoating of virus
    occurs in lysosomes in cytoplasm. Only the outer shell of
    virus is removed, and core-associated RNA transcriptase is
    activated.
   Gene expression : Reovirus cores contain all enzymes
    necs for transcribing, capping and extruding the mRNAs
    from the core, leaving the ds RNA genome inside.once
    extruded from the core, the mRNAs are translated into
    primary gene products.
   Replication: viral replicase is responsible for synthesis of
    negative-sense strands to form ds genome segments.
   Assembly of the correct complement segment is of
    unknown mechanism. May be self-assemble ?
Rotaviruses
   Major cause of diarrhoeal illness in infants and
    young animals including calves and piglets.
   Similar morphology and replication as Reovirus.
   There are 5 groups (AE) based on antigenic
    epitopes of the internal structural protein VP6, with
    Group A is the most frequent human pathogen.
   Outer capsids VP4 and VP7 are important
    neutralising antigens.
Pathogenesis
   Rotaviruses infect cells in the villi of the small
    intestine (gastric and colonic mucosa are spared).
   Multiply in cytoplasm of enterocytes and damage
    their transport mechanisms.
   NSP4- a viral enterotoxin induces secretion by
    triggering a signal transduction pathway. Damaged
    cells may slough into lument and released as stools.
   Diarrhoea may be due to impaired sodium and
    glucose absorption as damaged cells on villi are
    replaced by non-absorbing immature crypt cells. It
    may take 3-8 wks for normal function to be restored.