Overview of Hepatitis Virus
Virus Virus group Nucleic
acid Mode of infection Severity(chronicity) HAV Enterovirus
72(heptovirus) RNA Fecal-oral +(acute) HBV hepadnavirus DNA Percutaneous;
Permucosal ++(chronic) HCV Flavivirus RNA
Blood(transfusion-associated)
+ (chronic)
HDV B-dependent
small virus RNA blood + (chronic) HEV Calicivirus RNA Fecal-oral +(acute)
Viral Hepatitis - Overview
Viral Hepatitis - Overview
A
A BB CC DD EE
Source of virus feces blood/ blood-derived body fluids blood/ blood-derived body fluids blood/ blood-derived body fluids feces Route of transmission fecal-oral percutaneous permucosal percutaneous permucosal percutaneous permucosal fecal-oral Chronic
infection no yes yes yes no
Prevention pre/post-exposure immunization pre/post-exposure immunization blood donor screening; risk behavior modification pre/post-exposure immunization; risk behavior modification ensure safe drinking water
Type of Hepatitis
Human cytomegalovirus Epstein-Barr virus
Herpes simplex virus Yellow fever virus
Structure
Small,
non-enveloped icosahedral particle,
27 nm in
diameter
Replication
Unlike other picornaviruses, however, HAV is not
cytolytic and is released by exocytosis.
Laboratory isolates of HAV have been adapted to
Resistance
Stable to:
acid at pH 3
Solvents(ether,chloroform) detergents
saltwater,groundwater(months) drying(stable)
temperature
4℃: weeks
56℃for 30minutes: stable
Resistance
Inactivated by:
chlorine treatment of drinking water
formalin(0.35%,37℃,72hours)
acetic acid(2%,4hours)
B-propiolactone 丙丙丙 (0.25%,1hours)
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,
Concentration of Hepatitis A Virus in Various Body Fluids
Concentration of Hepatitis A Virus in Various Body Fluids
Source: Viral Hepatitis and Liver Disease 1984;9-22 J Infect Dis 1989;160:887-890
Feces Serum Saliva Urine B o d y F lu id B o d y F lu id
Infectious Doses per ml
Infectious Doses per ml
Geographic Distribution of HAV
Infection
Geographic Distribution of HAV
Infection
Anti-HAV Prevalence
High
Intermediate Low
Age-specific Mortality Due to
Hepatitis A
Age-specific Mortality Due to
Hepatitis A
Age group (years) Case-Fatality (per 1000) <5 3.0 5-14 1.6 15-29 1.6 30-49 3.8 >49 17.5 TotalTotal 4.14.1
Hepatitis A - Clinical
Features
Hepatitis A - Clinical
Features
Incubation period
Average 30 days Range 15-50 days
Jaundice by age group
<6 yrs <10% 6-14 yrs 40%-50%
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:
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
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
Immunity
Laboratory Diagnosis
Viral particles in the stool, by electron microscopy
Specific IgM in serum
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.
Introduction
approximately 350 million people are infected
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
Structure
Dane particle, is 42 nm in
diameter.
Resist to treatment with: ether, a
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
Structure
15-25nm
20×20×200nm 42nm
28nm
HBsAg
HBcAg
HBeAg
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
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
Global Patterns of Chronic HBV Infection
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
Concentration of Hepatitis B
Virus
in Various Body Fluids
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
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
Hepatitis B - Clinical
Features
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
Outcome of Hepatitis B Virus Infection by Age at Infection
Outcome of Hepatitis B Virus Infection by Age at Infection
Symptomatic Infection
Chronic Infection
Age at Infection
C h ro n ic I n fe ct io n ( % ) S ym p to m at ic In fe ct io n ( % )
Pathogenesis(1)
The virus starts to replicate within 3 days of its
acquisition,
Symptoms may not be observed for 45 days of
Pathogenesis(2)
Hypoimmune response.
IFN↓,HLA-I↓→CTL↓(An insufficient T-cell response )
Cell mediated immunopathogenic damage.
Pathogenesis (3)
Immune complexes formed between HBsAg and
Pathogenesis(4)
Pathogenic damage caused by autoimmunity
liver specific protein(LSP)
Viral variation
Major
eterminants of
acute and chronic
Clinical
outcomes of
acute
Typical Serologic Course
Acute Hepatitis B Virus Infection with Recovery
Typical Serologic Course
Acute Hepatitis B Virus Infection with Recovery Weeks after Exposure Weeks after Exposure Titer Titer Symptoms HBeAg anti-HBe Total anti-HBc
IgM anti-HBc anti-HBs
HBsAg
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
Typical Serologic Course
Progression to Chronic HBV Infection
Typical Serologic Course
Progression to Chronic HBV Infection
Weeks after Exposure
Weeks after Exposure
Titer Titer IgM anti-HBc Total anti-HBc HBsAg Acute (6 months) HBeAg Chronic (Years) anti-HBe
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
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
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
Diagnosis
Detection of serum HBVDNA: nucleic
hybridization; PCR.
Treatment
Interferon-alpha may be effective for treating
a chronic HBV infection.
Hepatitis B immune globulin may be
• Prevent chronic HBV Infection • Prevent chronic liver disease
• Prevent primary hepatocellular
carcinoma
• Prevent acute symptomatic HBV
infection
Elimination of Hepatitis B Virus
Transmission
Elimination of Hepatitis B Virus
Transmission
• Prevent perinatal 丙丙丙丙 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
Elimination of Hepatitis B Virus
Transmission
Elimination of Hepatitis B Virus
Transmission
㎝ ㎝ ㎝ ㎝ ㎝ ㎝ ㎝ ㎝ ㎝ ㎝ ㎝ ㎝ ㎝ ㎝
HBsAg HBeAg 丙 - HBs 丙 - HBe 丙 - HBc 丙 丙 丙 丙
丙 丙 丙 丙 丙 HBV丙 丙 丙 丙 丙 丙 丙 丙
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
Features of Hepatitis C Virus Infection
Features of Hepatitis C Virus Infection
Incubation period
Incubation period Average 6-7 weeksAverage 6-7 weeks Range 2-26 weeks
Range 2-26 weeks
Acute illness (jaundice)
Acute illness (jaundice) Mild (Mild (<<20%)20%) Case fatality rate
Case fatality rate LowLow Chronic infection
Chronic infection 75%-85%75%-85% Chronic hepatitis
Chronic hepatitis 70% (most asx)70% (most asx) Cirrhosis
Cirrhosis 10%-20%10%-20%
Mortality from CLD
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
Transmission
Blood transfusions, blood products organ donation
Intravenous drug abusers
community acquired: mechanism unclear. ? Vertical transmission ?
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
Clinical syndromes
HCV can cause acute infections but is more
likely to establish chronic infections.
Viremia
Chronic persistent hepatitis Chronic active hepatitiw
Cirrhosis
Chronic Hepatitis C
Factors Promoting Progression or Severity
Increased alcohol intake
Age > 40 years at time of infection
HIV co-infection
?Other
– Male gender
Serologic Pattern of Acute HCV Infection with Recovery
Symptoms
+/-Time after Exposure
T it er anti-HCV ALT Normal
0 1 2 3 4 5 6 1 2 3 4
Years Months
Serologic Pattern of Acute HCV Infection with Progression to Chronic Infection
Symptoms
+/-Time after Exposure
T it er anti-HCV ALT Normal
0 1 2 3 4 5 6 1 2 3 4
Years Months
HCV Prevalence by Selected Groups
United States
0 10 20 30 40 50 60 70 80 90
Hemophilia Injecting drug users
Surgeons, PSWs Hemodialysis
Average Percent Anti-HCV Positive Gen population adults
Military personnel STD clients
Laboratory diagnosis
1) Serology
Reliable serological tests have only recently become available.
HCV-specific IgG indicates exposure, not infectivity
Treatment, Prevention, and Control
Recombinant interferon-alpha is the only
known effective treatment for HCV.
Illicit drug abuse and transfusion are the most
Introduction
Defective virus which requires Hepatitis
B virus as a helper virus in order to replicate. Infection only occurs in
Structure
Virus particle 36
nm in diameter
encapsulated with HBsAg, derived from HBV
Delta antigen is
Hepatitis D (Delta) Virus
Hepatitis D (Delta) Virus
HBsAg
RNA
Replication
Transcription and replication of the HDV
genome are unusual. Specifically, the host cell’s RNA polymerase II makes an RNA copy,
Geographic Distribution of HDV Infection
Geographic Distribution of HDV Infection
HDV Prevalence High
Intermediate Low
Very Low No Data
Taiwan
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
Clinical Syndromes
•
Coinfection
– severe acute disease
– low risk of chronic infection
•
Superinfection
– usually develop chronic HDV infection
– high risk of severe chronic liver
disease
Hepatitis D - Clinical
Features
HBV - HDV Coinfection
HBV - HDV Coinfection
Typical Serologic Course
Typical Serologic Course
Time after Exposure Time after Exposure T it e r T it e r anti-HBs Symptoms ALT Elevated Total anti-HDV IgM anti-HDV
HDV RNA
HBV - HDV Superinfection
HBV - HDV Superinfection
Typical Serologic Course
Typical Serologic Course
Time after Exposure Time after Exposure T it e r T it e r Jaundice Symptoms
ALT Total anti-HDV
IgM anti-HDV HDV RNA
Laboratory Diagnosis
•
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 D - Prevention
Structure and Genome
30-32nm non-enveloped particle
s/s (+)sense RNA genome , ~7.5Kb.
Genetic organization similar (not identical) to
Hepatitis E - Clinical
Features
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
Geographic Distribution of
Hepatitis E
•
Most outbreaks associated with
fecally contaminated drinking
water
•
Minimal person-to-person
transmission
Hepatitis E -
Epidemiologic Features
Hepatitis E -
• 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?
Prevention and Control Measures
for Travelers to HEV-Endemic
Regions
Prevention and Control Measures
for Travelers to HEV-Endemic
Epidemiology
The delta agent infects children and adults
