Hepatitis virus
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)
HGV? RNA Blood?
Viral Hepatitis - Overview
A B C D E
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
? 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
Source,Viral Hepatitis and Liver Disease 1984;9-22
J Infect Dis 1989;160:887-890
Feces
Serum
Saliva
Urine
Bo
dy
F
lu
id
Infectious Doses per ml
100 102 104 106 108 1010
Geographic Distribution of HAV Infection
Anti-HAV Prevalence
High
Intermediate
Low
Very Low
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
Total 4.1
Source,Viral Hepatitis Surveillance Program,1983-1989
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%
>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
20× 20× 200nm
42nm
28nm
HBsAg
HBcAg
HBeAg
DNA
? 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
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,
? 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
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
Detectable
Urine,Feces,Sweat,Tears,Breast milk
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%
Outcome of Hepatitis B Virus Infection
by Age at Infection
Symptomatic Infection
Chronic Infection
Age at Infection
Ch
ro
nic
In
fec
tio
n
(%
)
Sy
mp
to
ma
tic
In
fec
tio
n
(%
)
Birth 1-6 months 7-12 months 1-4 years Older Children
and Adults
0
20
40
60
80
100 100
80
60
40
20
0
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
Weeks after Exposure
Titer
Symptoms
HBeAg anti-HBe
Total anti-HBc
IgM anti-HBc anti-HBs HBsAg
0 4 8 12 16 20 24 28 32 36 52 100
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
Weeks after Exposure
Titer
IgM anti-HBc
Total anti-HBc
HBsAg
Acute
(6 months)
HBeAg
Chronic
(Years)
anti-HBe
0 4 8 12 16 20 24 28 32 36 52 Years
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,
? Prevent chronic HBV Infection
? Prevent chronic liver disease
? Prevent primary hepatocellular carcinoma
? Prevent acute symptomatic HBV infection
Elimination of Hepatitis B Virus Transmission
Objectives
? 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
Elimination of Hepatitis B Virus Transmission Strategy
病 毒 抗 原 抗 体 系 统 检 测 结 果 分 析
H B s A g H B e A g 抗 - H B s 抗 - H B e 抗 - H B c 结 果 分 析
＋ － － － － H B V 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
Symptoms +/-
Time after Exposure
Tit
er
anti-HCV
ALT
Normal
0 1 2 3 4 5 6 1 2 3 4
Years Months
HCV RNA
Serologic Pattern of Acute HCV Infection with
Progression to Chronic Infection
Symptoms +/-
Time after Exposure
Tit
er
anti-HCV
ALT
Normal
0 1 2 3 4 5 6 1 2 3 4
Years Months
HCV RNA
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
Pregnant women
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
HBsAg
RNA
d antigen
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
HDV Prevalence
High
Intermediate
Low
Very Low
No Data
Taiwan
Pacific Islands
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
? 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
Typical Serologic Course
Time after Exposure
Ti
te
r anti-HBs
Symptoms
ALT Elevated
Total anti-HDV
IgM anti-HDV
HDV RNA
HBsAg
HBV - HDV Superinfection
Typical Serologic Course
Time after Exposure
Ti
te
r
Jaundice
Symptoms
ALT Total anti-HDV
IgM anti-HDV
HDV RNA
HBsAg
Laboratory Diagnosis
? Detect the delta antigen of antibodies
? ELISA and RIA
? 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
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
? Most outbreaks associated with
fecally contaminated drinking water
? Minimal person-to-person transmission
Hepatitis E - Epidemiologic Features
? 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
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,
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)
HGV? RNA Blood?
Viral Hepatitis - Overview
A B C D E
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
? 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
Source,Viral Hepatitis and Liver Disease 1984;9-22
J Infect Dis 1989;160:887-890
Feces
Serum
Saliva
Urine
Bo
dy
F
lu
id
Infectious Doses per ml
100 102 104 106 108 1010
Geographic Distribution of HAV Infection
Anti-HAV Prevalence
High
Intermediate
Low
Very Low
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
Total 4.1
Source,Viral Hepatitis Surveillance Program,1983-1989
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%
>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
20× 20× 200nm
42nm
28nm
HBsAg
HBcAg
HBeAg
DNA
? 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
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,
? 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
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
Detectable
Urine,Feces,Sweat,Tears,Breast milk
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%
Outcome of Hepatitis B Virus Infection
by Age at Infection
Symptomatic Infection
Chronic Infection
Age at Infection
Ch
ro
nic
In
fec
tio
n
(%
)
Sy
mp
to
ma
tic
In
fec
tio
n
(%
)
Birth 1-6 months 7-12 months 1-4 years Older Children
and Adults
0
20
40
60
80
100 100
80
60
40
20
0
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
Weeks after Exposure
Titer
Symptoms
HBeAg anti-HBe
Total anti-HBc
IgM anti-HBc anti-HBs HBsAg
0 4 8 12 16 20 24 28 32 36 52 100
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
Weeks after Exposure
Titer
IgM anti-HBc
Total anti-HBc
HBsAg
Acute
(6 months)
HBeAg
Chronic
(Years)
anti-HBe
0 4 8 12 16 20 24 28 32 36 52 Years
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,
? Prevent chronic HBV Infection
? Prevent chronic liver disease
? Prevent primary hepatocellular carcinoma
? Prevent acute symptomatic HBV infection
Elimination of Hepatitis B Virus Transmission
Objectives
? 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
Elimination of Hepatitis B Virus Transmission Strategy
病 毒 抗 原 抗 体 系 统 检 测 结 果 分 析
H B s A g H B e A g 抗 - H B s 抗 - H B e 抗 - H B c 结 果 分 析
＋ － － － － H B V 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
Symptoms +/-
Time after Exposure
Tit
er
anti-HCV
ALT
Normal
0 1 2 3 4 5 6 1 2 3 4
Years Months
HCV RNA
Serologic Pattern of Acute HCV Infection with
Progression to Chronic Infection
Symptoms +/-
Time after Exposure
Tit
er
anti-HCV
ALT
Normal
0 1 2 3 4 5 6 1 2 3 4
Years Months
HCV RNA
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
Pregnant women
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
HBsAg
RNA
d antigen
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
HDV Prevalence
High
Intermediate
Low
Very Low
No Data
Taiwan
Pacific Islands
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
? 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
Typical Serologic Course
Time after Exposure
Ti
te
r anti-HBs
Symptoms
ALT Elevated
Total anti-HDV
IgM anti-HDV
HDV RNA
HBsAg
HBV - HDV Superinfection
Typical Serologic Course
Time after Exposure
Ti
te
r
Jaundice
Symptoms
ALT Total anti-HDV
IgM anti-HDV
HDV RNA
HBsAg
Laboratory Diagnosis
? Detect the delta antigen of antibodies
? ELISA and RIA
? 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
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
? Most outbreaks associated with
fecally contaminated drinking water
? Minimal person-to-person transmission
Hepatitis E - Epidemiologic Features
? 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
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,
