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					Hepatitis virus
        Overview of Hepatitis Virus
Virus   Virus group      Nucleic   Mode of infection    Severity
                         acid                           (chronicity)
HAV     Enterovirus      RNA       Fecal-oral           +(acute)
        72(heptovirus)
HBV     hepadnavirus     DNA       Percutaneous;        ++(chronic)
                                   Permucosal
HCV     Flavivirus       RNA       Blood(transfusion-   + (chronic)
                                   associated)
HDV     B-dependent      RNA       blood                + (chronic)
        small virus
HEV     Calicivirus      RNA       Fecal-oral           +(acute)
HGV     ?                RNA       Blood                ?
               Viral Hepatitis - Overview
                                     Type of Hepatitis
                   A               B             C              D               E
Source of         feces           blood/        blood/        blood/           feces
virus                         blood-derived blood-derived blood-derived
                               body fluids   body fluids   body fluids
Route of        fecal-oral    percutaneous percutaneous percutaneous         fecal-oral
transmission                   permucosal   permucosal   permucosal

Chronic            no             yes            yes            yes             no
infection

Prevention       pre/post-      pre/post-     blood donor     pre/post-     ensure safe
                 exposure       exposure       screening;    exposure         drinking
               immunization   immunization   risk behavior immunization;       water
                                              modification risk behavior
                                                             modification
    Human cytomegalovirus
      Epstein-Barr virus

     Herpes simplex virus

      Yellow fever virus

          Rubella.
Hepatitis A virus
                  Structure

   Small, non-
    enveloped
    icosahedral
    particle,
   27 nm in
    diameter
    ssRNA
                      Replication
   Unlike other picornaviruses, however, HAV is not
    cytolytic and is released by exocytosis.
   Laboratory isolates of HAV have been adapted to
    growth in primary and continuous monkey kidney cell
    lines, but clinical isolates are very difficult to grow in
    cell culture.
                      Resistance
Stable to:
      acid at pH 3
      Solvents(ether,chloroform)
      detergents
      saltwater,groundwater(months)
      drying(stable)
      temperature
            4℃: weeks
            56℃for 30minutes: stable
            61℃for 20minutes: partial inactivation
                  Resistance
Inactivated by:
     chlorine treatment of drinking water
     formalin(0.35%,37℃,72hours)
     acetic acid(2%,4hours)
     B-propiolactone丙内酯(0.25%,1hours)
     Ultraviolet radiation(2μW/㎝2/min)
         Hepatitis A Virus Transmission

   Virus can be transmitted via fecal-oral route
    ingestion of contaminated food and water can
    cause infection
   HAV in shellfish is from sewage-contaminated
    water
   Virus can be transmitted by food handlers, day-
    care workers, and children.
                                Concentration of Hepatitis A Virus
                                    in Various Body Fluids

               Feces
Body Fluid




               Serum

               Saliva


                Urine


                     100           102            104              106   108   1010
                                             Infectious Doses per ml

             Source: Viral Hepatitis and Liver Disease 1984;9-22
                     J Infect Dis 1989;160:887-890
   Geographic Distribution of HAV Infection




Anti-HAV Prevalence
     High
     Intermediate
     Low
     Very Low
Age-specific Mortality Due to Hepatitis A

                         Age group                Case-Fatality
                          (years)                  (per 1000)

                             <5                        3.0
                            5-14                       1.6
                           15-29                       1.6
                           30-49                       3.8
                            >49                       17.5
                           Total                       4.1
 Source: Viral Hepatitis Surveillance Program, 1983-1989
     Hepatitis A - Clinical Features

                          Average 30 days
Incubation period         Range 15-50 days

Jaundice by         <6 yrs            <10%
age group
                    6-14 yrs        40%-50%
                    >14 yrs         70%-80%
          Hepatitis A - Clinical Features

   Milder disease than Hepatitis B;
   asymptomatic infections are very common,
    especially in children.
   Adults, especially pregnant women, may develop
    more severe disease
   no chronic form of the disease.
   Complications:
    Fulminant hepatitis is rare: 0.1% of cases
Pathogenesis
             Pathogenesis of HAV

 HAV replicates slowly in the liver without
  producing apparent cytopathological effects
  (CEPs). In the absence of cytolysis, the virus
  readily establishes a persistent infection.
 Jaundice, resulting from damage to the liver


 Antibody is detected and cell-mediated immune

  responses to the virus
                    For example

   An epidemic of HAV that occurred in Shanghai, China,
    in 1988 in which 300,000 people were infected with the
    virus resulted from eating Anadara subcrenata
     obtained from a polluted river.
Time course of HAV infection
                       Immunity


   Antibody protection against reinfection is lifelong
                  Laboratory Diagnosis

   Viral particles in the stool, by electron microscopy

   Specific IgM in serum

   PCR HAV-specific sequences in stool
          Treatment, Prevention and Control

   Prophylaxis with immune serum globulin given before
    or early in the incubation period

   A killed HAV vaccine has been approved and is
    available for use in children and adults at high risk for
    infection.

   A live HAV vaccine has been developed in China.
Hepatitis B virus
                  Introduction

   approximately 350 million people are infected
                globally with HBV.
                        Structure
   Small, enveloped DNA

   The genome: a small, circular, partly double-stranded
    DNA of 3200 base

   Although a DNA virus, it encodes a reverse transcriptase
    and replicates through an RNA intermediate.
                             Structure
   Dane particle, is 42 nm in
    diameter.
   Resist to treatment with: ether, a
    low pH, freezing, and moderate
    heating. This helps transmission
    from one person to another.
         Decoy Particles
   HBsAg-containing particles
    are released into the serum of
    infected people and
    outnumber the actual virions.
   Spherical or filamentous
   They are immunogenic and
    were processed into the first
    commercial vaccine against
    HBV.
Structure
               HBcAg HBsAg HBeAg
                  15-25nm
         42nm


HBsAg           20×20×200nm




         28nm

 HBcAg


                            DNA


HBeAg
                     Replication
   HBV has a very defined tropism for the liver.
   Its small genome also necessitates economy, as
    illustrated by the pattern of its transcription and
    translation.
   In addition, HBV replicates through an RNA
    intermediate and produces and release antigenic
    decoy particles.
                        Replication
   The entire genome can also be integrated into the host
    cell chromatin.
   HBsAg, but not other proteins, can often be detected in
    the cytoplasm of cells containing integrated HBV DNA.
   The significance of the integrated DNA in the replication
    of the virus is not known, but integrated viral DNA has
    been found in hepatocellular carcinomas.
Global Patterns of Chronic HBV Infection

    High (>8%): 45% of global population
      – lifetime risk of infection >60%
      – early childhood infections common
    Intermediate (2%-7%): 43% of global population
      – lifetime risk of infection 20%-60%
      – infections occur in all age groups
    Low (<2%): 12% of global population
      – lifetime risk of infection <20%
      – most infections occur in adult risk groups
High-risk groups for HBVinfection
   People from endemic regions
   Babies of mothers with chronic HBV
   Intravenous drug abusers
   People with multiple sex partners
   Hemophiliacs and other patients requiting blood and
    blood product treatments
   Health care personnel who have contact with blood
   Residents and staff members of institutions for the
    mentally retarded
 Concentration of Hepatitis B Virus
     in Various Body Fluids

High         Blood ,Serum, Wound exudates

Moderate     Semen, vaginal and menstrual
             secretions, Saliva, amniotic fluid
Low/Not      Urine , Feces, Sweat , Tears , Breast milk
Detectable
What determines the development of chronic vs.
               acute infection
        Age (chronic infections decrease with increasing age)
        Sex:
         Syndrome:           Males : Females
         Chronic Infection:       1.5 : 1
           Cirrhosis:              3:1
           PHC:                      6:1
        Route of infection (oral/sexual infections give rise to
         less chronic cases than serum infection
      Hepatitis B - Clinical Features
• Incubation period:           Average 60-90 days
                               Range 45-180 days
• Clinical illness (jaundice): <5 yrs, <10%
                               >5 yrs, 30%-50%
• Acute case-fatality rate:       0.5%-1%
• Chronic infection:          <5 yrs, 30%-90%
                              >5 yrs, 2%-10%
• Premature mortality from
  chronic liver disease:   15%-25%
                        100
                               Outcome of Hepatitis B Virus Infection                       100
                                       by Age at Infection




                                                                                                   Symptomatic Infection (%)
Chronic Infection (%)




                        80                                                                  80


                        60                                                                  60
                                                          Chronic Infection

                        40                                                                  40


                        20                                                                  20

                                      Symptomatic Infection
                          0                                                                  0
                              Birth   1-6 months    7-12 months       1-4 years   Older Children
                                                                                    and Adults
                                                   Age at Infection
                Pathogenesis(1)

   The virus starts to replicate within 3 days of its
    acquisition,
   Symptoms may not be observed for 45 days of
    longer, depending on the infectious dose, the
    route of infection, and the person.
                  Pathogenesis(2)

   Hypoimmune response.
     IFN↓,HLA-I↓→CTL↓(An insufficient T-cell response )
   Cell mediated immunopathogenic damage.
      CTL →acute hepatitis/chronic hepatitis
                   Pathogenesis (3)

   Immune complexes formed between HBsAg and anti-
    HBs contribute to the development of hypersensitivity
    reactions, leading to problems such as vasculitis血管炎,
    arthralgia关节痛, rash, and renal damage.
          Pathogenesis(4)


   Pathogenic damage caused by autoimmunity
     liver specific protein(LSP)
   Viral variation
       HBeAg
Clinical Syndromes
      Major
 eterminants of
acute and chronic
  HBV infection
Acute Infection
Symptoms of Acute Infection
   Clinical
outcomes of
    acute
 hepatitis B
  infection
The serological events associated with the typical course of acute
                          HBV disease
                 Typical Serologic Course
        Acute Hepatitis B Virus Infection with Recovery
                     Symptoms
                HBeAg                         anti-HBe


                                              Total anti-HBc
Titer

         HBsAg                      IgM anti-HBc                    anti-HBs




        0   4    8   12   16   20   24   28    32   36         52       100
                          Weeks after Exposure
                Chronic Infection

   Chronic hepatitis occurs in 5% to 10% of people
    with HBV infections, usually after mild or
    inapparent initial disease.
   Detected by the finding of elevated liver enzyme
    levels
Development of the chronic HBV carrier state
                               Typical Serologic Course
                    Progression to Chronic HBV Infection
                   Acute                        Chronic
                (6 months)                      (Years)
                                 HBeAg                       anti-HBe
                                         HBsAg
                                         Total anti-HBc
Titer



                                IgM anti-HBc




        0   4   8 12 16 20 24 28 32 36     52             Years
            Weeks after Exposure
      Primary Hepatocellular Carcinoma


   The WHO estimates that 80% of all cases of
    PHC can be attributed to chronic HBV
    infections.
   HBV may induce PHC by promoting continued
    liver repair and cell growth in response to
    tissue damage or by integrating into the host
    chromosome and stimulating cell growth
    directly.
                  Lab. Diagnosis

   The initial diagnosis of hepatitis can be made on
    the basis of the clinical symptoms and the
    presence of liver enzymes in the blood.
   The serology of infection describes the course
    and the nature of the disease.
   Acute and chronic HBV infect. Can be
    distinguished by the presence of HBsAg and
    HBeAg in the serum and the pattern of Ab to the
    individual HBV antigens.
                    Diagnosis

   During the symptomatic phase of infection,
    detection of antibodies to HBeAg and HBsAg is
    obscured because the antibody is complexed
    with antigen in the serum.
   The best way to diagnose a recent acute
    infection, especially during the period when
    neither HBsAg nor anti-HBs can be detected, is
    to measure IgM anti-HBc.
           Diagnosis


   Detection of serum HBVDNA: nucleic
    hybridization; PCR.
   Detection of viral DNA polymerase.
               Treatment

   Interferon-alpha may be effective for treating a
    chronic HBV infection.
   Hepatitis B immune globulin may be
    administered within a week of exposure and to
    newborn infants of HBsAg-positive mothers.
Elimination of Hepatitis B Virus Transmission

                  Objectives
   •   Prevent chronic HBV Infection
   •   Prevent chronic liver disease
   •   Prevent primary hepatocellular carcinoma
   •   Prevent acute symptomatic HBV infection
Elimination of Hepatitis B Virus Transmission
                      Strategy
    • Prevent perinatal围产期的HBV transmission
    • Routine vaccination of all infants
    • Vaccination of children in high-risk groups
    • Vaccination of adolescents
       – all unvaccinated children at 11-12 years of
         age
       – “high-risk” adolescents at all ages
    • Vaccination of adults in high-risk groups
        病毒抗原抗体系统检测结果分析
HBsAg   HBeAg   抗- HBs   抗- HBe   抗- HBc      结果分析

 +        -       -        -        -      HBV感染或无症状携带
                                           者
 +        +       -        -        -      急性或慢性乙型肝炎,
                                           或无症状携带者

 +        +       -        -        +      急性或慢性乙型肝炎
                                           ( 传染性强,“大三阳”)

 +        -       -        +        +      急性感染趋向恢复
                                           ( “小三阳”)

 -        -       +        +        +      既往感染恢复期

 -        -       +        +        -      既往感染恢复期

 -        -       -        -        +      既往感染或“窗口期”

 -        -       +        -        -      既往感染或接种过疫苗
Hepatitis C Virus
                   Introduction

   The major cause of parenterally transmitted
    non A non B hepatitis. It eluded identification
      for many years. In 1989, the genome was
        cloned from the serum of an infected
                   chimpanzee.
   Features of Hepatitis C Virus Infection
Incubation period          Average 6-7 weeks
                           Range 2-26 weeks
Acute illness (jaundice)   Mild (<20%)
Case fatality rate         Low
Chronic infection          75%-85%
Chronic hepatitis          70% (most asx)
Cirrhosis                  10%-20%
Mortality from CLD         1%-5%
(chronic liver disease )
              Common characteristics


   Putative Togavirus related to the Flavi and
    Pesti viruses.Thus probably enveloped.

   Has a ssRNA genome

   Does not grow in cell culture, but can infect
    Chimpanzees
                  Transmission

   Blood transfusions, blood products
   organ donation
   Intravenous drug abusers
   community acquired: mechanism unclear. ?
   Vertical transmission ?
   sexual intercourse
                  Epidemiology

   Causes a milder form of acute hepatitis than
    does hepatitis B
   But 50% individuals develop chronic infection,
    following exposure.
   Incidence endemic world-wide; high incidence
    in Japan, Italy and Spain
               Clinical syndromes

   HCV can cause acute infections but is more
    likely to establish chronic infections.
   Viremia
   Chronic persistent hepatitis
   Chronic active hepatitiw
   Cirrhosis
   Liver failure
           Chronic Hepatitis C
Factors Promoting Progression or Severity
   Increased alcohol intake
   Age > 40 years at time of infection
   HIV co-infection
   ?Other
    – Male gender
    – Other co-infections (e.g., HBV)
  Serologic Pattern of Acute HCV Infection
               with Recovery
                                                      anti-HCV
                Symptoms +/-


                    HCV RNA
Titer




                                   ALT


                          Normal
        0   1   2     3    4   5    6    1   2    3   4
                    Months                    Years
                       Time after Exposure
Serologic Pattern of Acute HCV Infection with
      Progression to Chronic Infection
                                                       anti-HCV
                 Symptoms +/-


                       HCV RNA
 Titer




                                                       ALT



                                 Normal
         0   1   2     3    4    5   6    1   2    3   4
                     Months                    Years
                        Time after Exposure
        HCV Prevalence by Selected Groups
                 United States
          Hemophilia
  Injecting drug users
        Hemodialysis
          STD clients
Gen population adults
     Surgeons, PSWs
     Pregnant women
   Military personnel

                        0   10    20   30    40    50   60   70    80   90
                                 Average Percent Anti-HCV Positive
              Laboratory diagnosis

   1) Serology
    Reliable serological tests have only recently
    become available.
    HCV-specific IgG indicates exposure, not
    infectivity
   2) PCR detects viral genome in patient's serum
      Treatment, Prevention, and Control

   Recombinant interferon-alpha is the only
    known effective treatment for HCV.
   Illicit drug abuse and transfusion are the most
    identifiable sources of HCV viruses.
Hepatitis D virus
                   Introduction

   Defective virus which requires Hepatitis B virus
    as a helper virus in order to replicate. Infection
    only occurs in patients who are already infected
                    with Hepatitis B.
                        Structure

   Virus particle 36
    nm in diameter
    encapsulated with
    HBsAg, derived
    from HBV
   Delta antigen is
    associated with
    virus particles
    ssRNA genome
        Hepatitis D (Delta) Virus
d antigen         HBsAg




                  RNA
                     Replication

   Transcription and replication of the HDV
    genome are unusual. Specifically, the host cell’s
    RNA polymerase II makes an RNA copy,
    replicates the genome, and makes mRNA.
       Geographic Distribution of HDV Infection




                                           Taiwan
                                            Pacific Islands


HDV Prevalence
     High
     Intermediate
     Low
     Very Low
     No Data
                   Pathogenesis

   Spread in blood, semen, and vaginal secretion.
   It can replicate and cause disease only in
    people with active HBV infections.
   Replication of the delta agent results in
    cytotoxicity and liver damage.
               Clinical Syndromes

   Increases the severity of HBV infections.
   Fulminant hepatitis
     Hepatitis D - Clinical Features

• Coinfection
  –severe acute disease
  –low risk of chronic infection
• Superinfection
  –usually develop chronic HDV infection
  –high risk of severe chronic liver disease
        HBV - HDV Coinfection
          Symptoms        Typical Serologic Course
         ALT Elevated



                                         anti-HBs
Titer




          IgM anti-HDV



        HDV RNA

             HBsAg
                                  Total anti-HDV


                Time after Exposure
        HBV - HDV Superinfection
          Jaundice
                         Typical Serologic Course
              Symptoms

                                      Total anti-HDV
                ALT
Titer




                         HDV RNA
               HBsAg


                                      IgM anti-HDV


                Time after Exposure
              Laboratory Diagnosis

   Detect the delta antigen of antibodies
   ELISA and RIA
      Hepatitis D - Prevention

• HBV-HDV Coinfection
  Pre or postexposure prophylaxis to prevent
   HBV infection
• HBV-HDV Superinfection
  Education to reduce risk behaviors among
   persons with chronic HBV infection
Hepatitis E Virus
              Structure and Genome

   30-32nm non-enveloped particle
   s/s (+)sense RNA genome , ~7.5Kb.
   Genetic organization similar (not identical) to
    Caliciviruses
      Hepatitis E - Clinical Features

• Incubation period:     Average 40 days
                         Range 15-60 days
• Case-fatality rate:    Overall, 1%-3%
                      Pregnant women, 15%-25%
• Illness severity:    Increased with age
• Chronic sequelae:    None identified
Geographic Distribution of Hepatitis E
          Hepatitis E -
     Epidemiologic Features

• Most outbreaks associated with
  fecally contaminated drinking water
• Minimal person-to-person transmission
Prevention and Control Measures for
Travelers to HEV-Endemic Regions
• Avoid drinking water (and beverages with ice) of
  unknown purity, uncooked shellfish, and uncooked
  fruit/vegetables not peeled or prepared by traveler
• IG prepared from donors in Western countries does
  not prevent infection
• Unknown efficacy of IG prepared from donors in
  endemic areas
• Vaccine?
                  Epidemiology

   The delta agent infects children and adults
    with underlying HBV infection, and people
    who are persistently infected with both HBV
    and HDV are a source for the virus.

				
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