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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(transfusionassociated)

+ (chronic)

HDV

B-dependent small virus

RNA

blood

+ (chronic)

HEV

Calicivirus

RNA

Fecal-oral

+(acute)

HGV

?

RNA

Blood

?


Viral Hepatitis - Overview Type of Hepatitis

A Source of virus Route of transmission Chronic infection Prevention

B

C

D

E

feces

blood/ blood/ blood/ blood-derived blood-derived blood-derived body fluids body fluids body fluids

feces

fecal-oral

percutaneous percutaneous percutaneous permucosal permucosal permucosal

fecal-oral

no

yes

pre/postexposure immunization

pre/postexposure immunization

yes

yes

blood donor pre/postscreening; exposure risk behavior immunization; modification risk behavior modification

no ensure safe drinking water


Human cytomegalovirus  Epstein-Barr virus  Herpes simplex virus  Yellow fever virus  Rubella.


Hepatitis A virus


Structure 

Small, nonenveloped icosahedral particle, 27 nm in diameter ssRNA


Replication ď Ž

ď Ž

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, daycare workers, and children.


Body Fluid

Concentration of Hepatitis A Virus in Various Body Fluids Feces

Serum Saliva

Urine

100

102

104

106

Infectious Doses per ml Source: Viral Hepatitis and Liver Disease 1984;9-22 J Infect Dis 1989;160:887-890

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)

<5 5-14 15-29 30-49 >49 Total

Case-Fatality (per 1000)

3.0 1.6 1.6 3.8 17.5 4.1

Source: Viral Hepatitis Surveillance Program, 1983-1989


Hepatitis A - Clinical Features Average 30 days Incubation period Jaundice by age group

Range 15-50 days <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 ď Ž

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 ď Ž

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 ď Ž

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 ď Ž

ď Ž

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

яБо

HBcAg HBsAg HBeAg


42nm HBsAg

15-25nm

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 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: • Chronic infection:

0.5%-1% <5 yrs, 30%-90% >5 yrs, 2%-10%

• Premature mortality from chronic liver disease: 15%-25%


Outcome of Hepatitis B Virus Infection100 by Age at Infection 80

80

60

60

Chronic Infection

40

40

20

20 Symptomatic Infection

0 Birth

1-6 months

7-12 months

Age at Infection

1-4 years

0 Older Children and Adults

Symptomatic Infection (%)

Chronic Infection (%)

100


Pathogenesis(1) ď Ž

ď Ž

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 antiHBs 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)

ď Ž

ď Ž

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 anti-HBe

HBeAg

Total anti-HBc

Titer

0

4

anti-HBs

IgM anti-HBc

HBsAg

8

12

16

20

24

28

Weeks after

32

36

52

100


Chronic Infection ď Ž

ď Ž

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 (6 months)

Chronic (Years) HBeAg

anti-HBe HBsAg Total anti-HBc

Titer

IgM anti-HBc

0

4

8 12 16 20 24 28 32 36

Weeks after Exposure

52

Years


Primary Hepatocellular Carcinoma ď Ž

ď Ž

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 ď Ž

ď Ž

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 ď Ž

ď Ž

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 ď Ž

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 Acute illness (jaundice) Case fatality rate Chronic infection Chronic hepatitis Cirrhosis Mortality from CLD (chronic liver disease )

Average 6-7 weeks Range 2-26 weeks Mild (<20%) Low 75%-85% 70% (most asx) 10%-20% 1%-5%


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 +/-

Titer

HCV RNA

ALT

Normal 0

1

2

3 4 Months

5

6

1

Time after Exposure

2 3 Years

4


Serologic Pattern of Acute HCV Infection with Progression to Chronic Infection anti-HCV Symptoms +/-

Titer

HCV RNA

ALT

Normal 0

1

2

3 4 Months

5

6

1

Time after Exposure

2 3 Years

4


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 Average Percent Anti-HCV Positive

90


Laboratory diagnosis ď Ž

ď Ž

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 ď Ž

ď Ž

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 ď Ž

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 ď Ž

ď Ž

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 δ antigen

HBsAg

RNA


Replication ď Ž

Transcription and replication of the HDV genome are unusual. Specifically, the host cellâ&#x20AC;&#x2122;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 ď Ž ď Ž

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 Cours

Titer

ALT Elevated

IgM anti-HDV

antiHBs

HDV RNA HBsAg

Time after Exposure

Total antiHDV


HBV - HDV Superinfection Jaundice

Typical Serologic Course

Symptoms Total anti-HDV

Titer

ALT

HDV RNA HBsAg IgM anti-HDV

Time after Exposure


Laboratory Diagnosis ď Ž ď Ž

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: • Case-fatality rate:

Average 40 days Range 15-60 days 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 â&#x20AC;˘ Most outbreaks associated with fecally contaminated drinking water â&#x20AC;˘ 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 ď Ž

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.


Hepatitis virus