3. 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 ?
4. 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
9. 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.
10. 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
11. 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)
12. 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.
13. 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
15. Age-specific Mortality Due to Hepatitis A
Age C as e-
group
(ye ars Fatality
(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
16. 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%
17. 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
19. 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
20. 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.
23. Immunity
Antibody protection against reinfection is lifelong
24. Laboratory Diagnosis
Viral particles in the stool, by electron microscopy
Specific IgM in serum
PCR HAV-specific sequences in stool
25. 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.
27. Introduction
approximately 350 million people are infected
globally with HBV.
28. 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.
29. 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.
30. 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.
34. 15-25nm
42nm
HBsAg 20×20×200nm
28nm
HBcAg
DNA
HBeAg
35. 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.
36.
37.
38.
39. 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.
40. 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
41.
42. 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
43. 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
44. 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
45. 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%
46. Outcome of Hepatitis B Virus Infection 100
100
by Age at Infection
Symptomatic Infection (%)
80 80
Chronic Infection (%)
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
47. 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.
50. 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.
51. Pathogenesis(4)
Pathogenic damage caused by autoimmunity
liver specific protein(LSP)
Viral variation
HBeAg
59. 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
60. 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
63. 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
64. 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.
65. 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.
66. 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.
67.
68. Diagnosis
Detection of serum HBVDNA: nucleic
hybridization; PCR.
Detection of viral DNA polymerase.
69. 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.
71. 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
74. 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.
75. 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 )
76. 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
77.
78. Transmission
Blood transfusions, blood products
organ donation
Intravenous drug abusers
community acquired: mechanism unclear. ?
Vertical transmission ?
sexual intercourse
79. 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
80. 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
81. 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)
82. 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
83. 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
84.
85. 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
86. 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
87.
88.
89. 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.
91. 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.
92. Structure
Virus particle 36
nm in diameter
encapsulated with
HBsAg, derived
from HBV
Delta antigen is
associated with
virus particles
ssRNA genome
94. 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.
95. Geographic Distribution of HDV Infection
Taiwan
Pacific Islands
HDV Prevalence
High
Intermediate
Low
Very Low
No Data
96. 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.
97. Clinical Syndromes
Increases the severity of HBV infections.
Fulminant hepatitis
98. 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
99. HBV - HDV Coinfection
Symptoms Typical Serologic Course
ALT
Elevated
anti-
Titer
IgM anti-HDV HBs
HDV RNA
HBsAg
Total anti-
HDV
Time after
Exposure
100. HBV - HDV Superinfection
Jaundice
Typical Serologic Course
Symptoms
Total anti-HDV
ALT
Titer
HDV RNA
HBsAg
IgM anti-HDV
Time after
Exposure
102. 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
104. Structure and Genome
30-32nm non-enveloped particle
s/s (+)sense RNA genome , ~7.5Kb.
Genetic organization similar (not identical) to
Caliciviruses
105.
106. 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
109. Hepatitis E -
Epidemiologic Features
• Most outbreaks associated with
fecally contaminated drinking water
• Minimal person-to-person transmission
110. 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?
111. 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.
