HEPATITIS VIRUS

Efrida Warganegara
 HEPATITIS VIRUS
1. Hepatitis Virus A
2. Hepatitis Virus B
3. Hepatitis Virus C
4. Hepatitis Virus D
5. Hepatitis Virus E
6. Hepatitis Virus F
7. Hepatitis Virus G
8. T T Virus
 Introduction
 Hepatitis means inflammation and damage to the
liver, and can be caused by infection by various
organism, inclufing bacteria (leptospira sp.), viruses
(hepatitis A, B, dan C), or parasites (Schistosoma
mansoni)
 Viruses are the most common infectious causess of
hepatitis. at least 5 different viruses are referred to as
Hepatitis virus, and they generally cannot distinguish
clinically
 The disease may manifest as acute hepatitis (hepatitis A,
B, or E) or chronic hepatitis (hepatitis B or C).
 In hepatitis B or C infection, progressive liver damage,
liver failure, or even liver cancer may result.
 KEY CONCEPTS

Display marked tropism for liver cells

Use either :
“hit & run” infectious strategy
(Hepatitis virus A & E)
results in acute infection that is
cleared by the immune system
“hide & infiltrate” strategy
(Hepatitis virus B, C,
Delta, G)
lead to chronic infection
 KEY CONCEPTS
Cause similar symptoms during the acute
stage of infection that result of liver
damage
Can be identified by testing for presence of
specific viral proteins, specific antibodies
against these proteins or viral nucleic acid
Can be treated with agents such as
interferon, however treatment for chronic
carriers of hepatitis B, C, D and G generally
ineffective
Vaccine exist : A & B
 Viral Hepatitis - Historical Perspectives
“Infectious” Enterically
/ Catarrhal A E transmitted

Viral hepatitis NANB

“Serum” B D C Parenterally
transmitted

F, G, TTV
? other
 Virus Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E
Family Picornaviridae Hepadnaviridae Flaviviridae None Caliciviridae
Genus Hepatovirus Orthohepadna eHep-c-virus Deltavirus
virus (Unnamed)
Virion Icosahedral Spherical, Spherical, Spherical, Icosahedral,
27 nm 42 nm 30-60 nm 35 nm 27-34 nm
Envelope No Yes (HBsAg) Yes Yes(HBsAg) No
Genome ssRNA dsDNA ssRNA ssRNA ssRNA
Size 7,8 kb 3,2 kb 9,4 kb 1,7 kb 7,5 kb
Stability Heat & acid Acid-sensitive Eter-sensitive Acid-sensitive Heat-stable
stable Acid-sensitive
Transmission Faecal-oral Parenteral Parenteral Parenteral Faecal-oral
Prevalence High High Moderate Low, Regional
regional
Fulminant Rare Rare Rare Rare In
disease pregnancy
Chronic Never Often Often Often Never
disease
Oncogenic No Yes Yes ? No
 General symptoms of hepatitis virus infection
Acute inflammation chronic

Prodromal signs :
Fever
Gastrointestinal symptoms
Jaundice/ icteric
Hepatitis virus type A enteric
Hepatitis virus type E
acute
Hepatitis virus type B
parenteral
Hepatitis virus type C chronic
Hepatitis virus type D
cirrhosis
Hepatitis virus type G hepatocellular-Ca
 Introduction
 The disease picture is a febrille illness of prolong
duration marked by jaundice, fatique and malaise,
abdominal pain, loss of appetite, anorexia and nausea,
 Chronic hepatitis can be associated with a rash, due
to immune complex-associated vasculitis, and with
arthritis.
 Common risk factor include eating contaminated
seafood (hepatitis A), multiple sexual partners
unprotected intercouse (hepatitis B), intravenous
drug use (hepatitis C), or blood transfusion.
HEPATITIS ACUTE
ASYMPTOMATIC
FULMINANT
Severity of the disease depend on :
* virus type
* individual
More than ½ cases asymptomatically

Chronic hepatitis symptoms exist

increasing enzyme levels
> 6 months
Chronic persistent chronic active hepatitis
(mild)

Enzymes level cirrhosis

Normal hepatic failure
hepatocellular-Ca
 Introduction
 Clinical diagnosis on the basis of jaundice must be
confirmed by 1) liver function test : level of serum
aminotransferase, bilirubin and alkaline phosphatase;
and 2) hepatitis serologis : virus-specific antigen and
antibody markers in serum.
 Dramatic elevation of serum aminotransferase (alanine
dan aspartat aminotransferas) are characteristic of
acute viral hepatitis
 Specific laboratory test for hepatitis A and B viruses
have been available for some years, originally referred
to as ‘nonA-nonB” viruses are now becoming available.
 Introduction
 More than half the liver must be damaged or destroyed
before liver function fails.
 Regeneration of liver cells is rapid but fibrous repair, especially
when infection persist can lead to cirrhosis
 Managemen is mostly symptomatic,
 Except in the cases of hepatitis A and B, there are no licensed
vaccine, and
 although specific treatments are available chronic stage of
hepatitis B and C (e.g. interferron), there are no specific
treatmens for this disease.
 Chronic hepatitis C is the most common cause of liver failure
and subsequent liver transplantation
Control
Screening blood donor for
hepatitis viruses B, C
Immunization (active or
passive)
Treatment : Interferon
Antiviral drugs
 HEPATITIS A VIRUS (HAV)

• Discovered by Cockayne tahun 1912

• Cause infectious hepatitis, acute
• A distinct member of the Picornaviridae family (previously
Enterovirus 72), a new genus : Hepatovirus
• Only 1 serotype
• Ø 27 – 32 nm, spherical particle, cubic symetry
• Containing a linear ss-RNA genome with a size 7.5 kb,
surround by capsid consist of 4 polypeptide :
VP1 – VP4, nonenveloped
• The most likely mode of transmission : fecal-oral route
through close personal contact
• Acute infection, incubation period 2 – 6 weeks
Virus stability :
Virus is destroyed by :
 Autoclaving 121oC, 20 minutes
 Boiling in water for 5 minutes
 Oven (dry heat 1800C), for 1 hour
 UV irradiation, 1 minute at 1,1 watts
 Treatment with formalin 1 : 4000 for 3 days at
370C or chlorine 10 – 15 ppm, 30 minutes
Stable to treatment with 20% ether, acid (pH 1.0
for 2 hours)
Infectivity can be preserved
at least 1 month after being dried, and stores at
25oC and 42 % relative humidity
or for years at – 200C
LABORATORY DIAGNOSIS

• Virus particles have been detected by immune

electron microscopy in fecal extracts of
hepatitis A patients

• Virus appears early in the disease, and

disappears within 2 weeks following onset
of jaundice

• HAV can be detected in the liver, stool, bile, and

blood of naturally infected humans and
experimental infected nonhuman primates
by : PCR or Nucleic acid hybridization assay
Serology :
 IgM specific anti-HAV fraction appears
during the acute phase peaking about 2
weeks after elevation of liver enzyme
 Anti-HAV IgM usually decline to
undetectable levels within 3 – 6 months
 Anti-HAV IgG appears soon after the
onset of the disease and eventually
replace IgM
 IgG persist for decades
Methods for measuring Ab :
RPHA
ELISA
IMMUNOLOGIC AND BIOLOGIC EVENTS
ASSOCIATED WITH HAV INFECTION

Jaundice

Ig
M

Aminotransferases

Ig
VIF G

VIB

0 2 4 6 8 10 12
Weeks after exposure

VIF=virus in feces
VIB=virus in blood
 HEPATITIS B VIRUS (HBV)

Discovered by Blumberg (1923)

Patients & aborigin
Australian Ag.
Cause serum hepatitis
Australian antigen HBsAg
Family Hepadnaviridae
Genus Orthohepadna virus
HBV Morphology

Structure & antigen complex

3 shapes in serum
. Dane particles : Ø 42 nm
. Spherical particles : Ø 22 nm
. Filament particles : Ø 22 nm
Genome ds DNA polimerase 3200 bp
Spherical
Molecular weight 2 x 106 kd
 Hepatitis B virus particle

Virion 42 nm Nucleus Lysis nucleus

HBsAg / Dane virion 28 nm
virion (HBeAg)
particle HBcAg
Antigen structure :

1. HBsAg Anti-HBs

2. HBcAg Anti-HBc

3. HBeAg Anti-HBe
STABILITY
 Temperature – 20oC more than
20 years
 Dry, 25oC stay for 1 week
 Temperature 100oC, 1 minute
 pH 2,4 for 6 hours
 Sodium hypochlorite 5% for 3
minutes
Viral replication :

Attachment – Uncoating – DNA

within nucleus (transcription) –
mRNA (translation) – RNA
(reverse transcription) – cDNA –
re enter to previous cycle
 Attachment

Reenter cycle
Uncoating

Host DNA repair AAA Positive-

AAA
AAA strand
cccD DNA
NA mRNA synthesis

Nucle
us Translati
on Encapsidat
ion Negative-
Cytoplasm strand
3.5 kb
DNA
RNA synthesis
HBV replication cycle
MODE OF TRANSMISSION

- Parenteral

- Mucosal (per oral & sexual

contact)

- Vertically from mother to

baby
Laboratory examination

Isolation : cell culture difficult

Diagnosis :
Serology (Ag – Ab)
Transaminase enzyme (LFT)
Histology (biopsy)
PCR (molecular)
Electron Microscopy (virus particle)
Leucopenia during pre jaundice phase
 Prodrome,
Acute diseases Convalescence
Incubation Early
period
Important
HBsAg HBsAg IgM-anti HBc Anti HBs
diagnosis
IgG anti-HBc
tests
1 2 3 4 5 6 7 8 9
Relative Anti-HBc
concentration
of reactants

HBsAg Anti HBs

Level of HBeAg Anti-HBe
detection

Month after
exposure 1 2 3 4 5 6 7 8
ALT
Symptoms
Clinical and serologic events occurring in patient with acute
hepatitis B infection
 SEROLOGICAL INTERPRETATION OF HBV
INFECTION
Results Interpretation
HBsAg (+) Hepatitis B infection active, acute/ chronic
Anti-HBs (+) Protection to reinfection (immunity)
HBsAg (-) (+) after > 16 weeks, persist for years
Anti-HBc (+) Might be HBV active infection
Anti-HBs (-) Should be confirm IgM anti-HBc,  3 months
Total anti-HBc persist 5-6 years
HBeAg (+) Infectious active hepatitis, acute / chroni
HBsAg (+) Potential infectious
Anti-HBe (+) Non infectious blood
Carrier state
 Prevaccination screening hepatitis B
HBsAg (+) HBsAg (-) HBsAg (-) HBsAg (-) HBsAg (-)
Anti-HBs (-) Anti-HBs (-) Anti-HBs (+) Anti-HBs (+) Anti-HBs (-)
Anti-HBc (-/+) Anti-HBc (+) Anti-HBc (+/-) Anti-HBc (+/-) Anti-HBc (-)
Titer > 10 mU/ml Titer < 10 mU/ml

No Postpone No Booster Vaccination

Vaccination vaccination vaccination

LFT Check Measure titer Measure titer Measure titer

examination anti-HBs anti-HBs anti-HBs anti-HBs
3-6 months
 HEPATITIS C VIRUS (HCV)
NANB hepatitis virus parenteral
1960 - 1980 blood screening for HBV
post transfusion hepatitis
 First reported by HOUGHTON &BRADLEY
using molecular biology technique, and
virus clone (1984 )
 Family Flaviviridae
 Genus Hep-C-virus
 Mode of transmission
- Blood transfusion
- Sexual contact
 Incubation period 2 – 26 weeks ( 8 weeks)
Structure & composition

 ssRNA genome 9.4 kb, positive strand

 6 genotype :
(1a,b, 2a,b,c, 3a,b, 4, 5 and 6)
 enzyme specific to HCV & essential the
replication of the virus
 Protease
 RNA-dependent RNA Polymerase
 Helicase
Pat hology
 Clinical symptoms mild
 Elevation of liver enzymes mild
to moderate
 Disease develop to :
-Chronic infection
-Cirrrhosis
-Carcinoma
Laboratory diagnosis

 Specimen : blood & liver biopsy

 Microscopic : detection of virus
particle
 Tissue culture : can not grow
 Inoculation in chimpansee
 Serology : antibody detection anti-
HCV (ELISA)
 P C R : Molecular detection of
RNA virus
 Treatment :
 Interferon
 Ribavirin : synthetic guanosine nucleoside analog
with activity against a number of viruses

Ribavirin alone :
has only small effect on the biochemical
parameters of hepatic function & replication of
HCV combination with IFN-2b
 Hepatitis D Virus (HDV)
Reported first by RIZETTO, CANESE &
ARICO (1977)
Family?
Genus Deltavirus
Transmission : parenteral
parallel with HBV
Develop to chronic infection
Incubation period : 6 – 10 weeks
Structure & composition

 Genome : ssRNA 1.7 kb, Ø 35

– 37 nm
 Delta antigen surrounding by
HBsAg
 Defective virus, need hepatitis
B virus for replication
Hepatitis D virus particle surround by hepatitis B
virus particle
 Hepatitis E virus(HEV)

NANB hepatitis virus oral

Family Caliciviridae

Incubation period 3 – 7 weeks

Mode of transmission oral-fecal

Structure & composition
 Genome ssRNA 7.5 kb
 Ø 32 – 34 nm
 Positive strand
 Envelope
 Heat stable
 Clinical symptoms similar
with HAV infection
Laboratory diagnosis

Specimen : stool and liver biopsy

Electron microscopy : detection of

virus particle

Serology : Specific antibody in serum

fluorescence microscope

P C R : molecular
 Hepatitis F Virus (HFV)

 Reported in France at 1997

 Morphology
unclear
Other characteristics
 Hepatitis G virus(HGV)

The newest virus identified

Reported at 1995 – 1996
Family Flaviviridae
3 genotype :
GB-A
plant viruses
GB-B
GB-C human virus
Morphology :
- Genome RNA positive-strand,
2900 bp
◦ enzyme : RNA polimerase;
Helicase ; Protease
Mode of transmission parenteral
- Blood transfusion
- Transplantation
- Sexual contact (probably)
Might be single infection or with HBV/
HBC
Laboratory diagnosis

 P C R : molecular

 EM : virus particle

 Serology : antibody test

under development
 T T Virus
Reported in Japan, 1997
Hepatitis post transfusion
 New classification of virus
Family Circinoviridae
Similar with Circinoviridae : palnts &
vertebrates
 Morphology :
DNA virus ss linear, size30 – 50 nm
Non envelope, 3739 nucleotide
Fulminant hepatitis : chronic hepatitis
(unknown etiology)
“Cryptogenic liver disease” & pathogenic role ?
 Kepustakaan

1. Jawetz
2. Boyd
3. Human Virology  Leslie Collier and Jhons
Oxford