HEPATITIS VIRUS

Cucunawangsih
2013
CLASSIFICATION
RNA

DNA Single-stranded Double-stranded

Positive strand Negative strand

Single-stranded Double-stranded

Non-enveloped
Enveloped
Non-enveloped Enveloped icosahedral

Icosahedral
Caliciviridae
Hepadnaviridae
Flaviviridae
HEPATITIS E

HEPATITIS B
HEPATITIS C
Picorviridae

Classification of major viral agents causing hepatitis. HEPATITIS A

Adapted from Lippincott’s illustrated Review: Microbiology 2nd HEPATITIS D
CLASSIFICATION

Hepatitis
Antigen Corresponding Ab Comments
type
RNA virus; present in stool and serum early in
A Hepatitis A virus (HAV) Anti-HAV
course of hepatitis A
DNA virus; found in serum in > 90% of patients
Hepatitis B surface
Anti-HBs with acute hepatitis B; anti-HBs appears after
antigen (HBsAg)
infection and confers immunity
B Hepatitis B core antigen Anti-HBc detected in serum during and after
Anti-HBc
(HBcAg) acute infection
Hepatitis B envelope HBeAg correlates with infectivity; suggestive of
Anti-HBe
antigen (HBeAg) active viral replication
RNA virus; previously known as posttransfusion
C Hepatitis C antigen Anti-HCV
NANB hepatitis
D Hepatitis D antigen Anti-HDV Defective RNA virus; requires presence of HBsAg
RNA virus present in stool; cause enteric NANB
E Hepatitis E antigen Anti-HEV
hepatitis
Applied Therapeutics; ed.20; Koda-Kimble&Young
TRANSMISSION

Mode of transmission

Injection,
heterosexual
Fecal/oral
and homosexual sex

HAV HEV HBV HCV HDV

Acute infections Acute and/or chronic infections

Adapted from Lippincott’s illustrated Review: Microbiology 2nd

HEPATITIS A VIRUS
 Stable:
• 20% ether, acid (pH 1.0 for 2 hours), heat (600C for 1 hour)

Store at:
• 25 0 C with 42% relative humidity 1 month
• -200C years

Destroyed by:
autoclave (1210C, 20’), boiling 5’, dry heat (1800C, 1 hour),
UV 1.1 watts(1’), formalin 1:1000 (3 days, 370C),
chlorine 10-15 ppm (30’)

Heating food > 85 C, 1’ ; disinfecting surface with sodium hypo chloride

(1:100 dilution of chlorine bleach) are necessary to inactivate HAV
Important Properties of Hepatitis A Virus (Hepatovirus)
Classification Picornaviridae
Virus Icosahedral
Virion
28-30 nm in diameter (small particle)
Composition RNA

Single-stranded RNA, linier, positive sense, 7.2-8.4 kb in size,

Genome
infectious, contains genome-linked protein (VPg)

Four major polypeptides cleaved from a large precursor polyprotein.

Proteins Surface proteins VP1 and VP3 are major antibody-binding sites.
Internal protein VP4 is associated with viral RNA

Envelope None
Replication Cytoplasm
Variation One serotype
PATHOGENESIS

HAV tertelan, replikasi terjadi di mukosa usus diikuti periode
viremia masuk hepatosit

HAV melakukan uncoating untai RNA uncoated dan

protease virus

Terjadi sintesa protein dan HAV baru yang akan

meninggalkan hepatosit. Pada saat ini dapat ditemukan
infiltrasi limfosit dan pembentukan cytokine

Kerusakan sel hati kemungkinan karena sistem imun tubuh

dan dapat dilihat dari peningkatan SGOT dan SGPT

HAV: hepatitis A virus,
etiologic agent of infectious
hepatitis A

Anti HAV: Antibody to HAV

detecable at oncet of symtoms,
lifetime persistance

IgM anti-HAV:
IgM class antibody to HAV
indicates recent infection with
hepatitis A positive up to 4-6 month
after infection

There is no antigenic cross-reactivity with HBV or

other hepatitis viruses
DIAGNOSIS LABORATORIUM:

Isolation of HAV is not practical, but the virus can be detected
in fecal sample

IgM anti-HAV specific for acute infection

Total anti-HAV (IgM and IgG anti-HAV)

PREVENTION IMMUNOPROPHYLAXIS

Pre-exposure and Post-exposure

ACTIVE: Immunoglobulin

PASSIVE: Vaccine
Single (Havrix/Vaqta)
Combination (Twinrix) 18 years or older
HEPATITIS B VIRUS
 Stable:
• 370C for 60 minutes
• 260C 1 week
• -200C 20 years
• HBsAg stable at pH 2,4 for up to 6 hours,
but HBV infectivity is lost

Sodium hypo chloride 0,5% (1:10 chlorine bleach) destroyed

antigenicity within 3 minutes
Serum/blood specimen need higher concentration (5%)

HBsAg is not destroyed by UV

Important Properties of Hepatitis B virus
Classification Hepadnaviridae (hepatotropic DNA viruses)
Virus Virion 42 nm in diameter (nucleocapsid 18 nm)

Composition DNA
Double-stranded DNA, circular, 3.2 kb in size,
infectious, negative sense is full length and positive
Genome
sense is partially complete. The gap must be
complete at beginning of replication cycle
Two major polypeptides are present in HBsAg; one
Proteins
polypeptide is present in HBcAg
Envelope Contain HBsAg and lipid
In vivo replication: liver, lymphocytes, pancreas,
other organs.
Replication HBcAg in nucleus; HBsAg in cytoplasm; both mature
virus and 22 spherical particles consist of HBsAg
secreted from the cell surface
Genom of Hepadnavirus (Hepatitis B Virus)

Nucleic acid

Capsid

Envelope

C – the core protein

P – the polymerase
S – the 3 polypeptides of the surface antigen (pre S1, pre S2, and S)
X – a transactivator of viral transactivator of viral transcription
PATHOGENESIS

Pada saat terjadi infeksi HBV virion HBV dalam darah
akan berikatan dengan pHSA (“polymerized human serum
albumin)

Replikasi genom HBV berlangsung dalam hepatosit

menghasilkan virion utuh dan protein virus bebas seperti
HBsAg dan HBcAg

Timbulnya protein virus merangsang pembentukan antibodi

humoral dan seluler melalui proses “immune recognation”
yang melibatkan antigen presenting cells (APC)
PATHOGENESIS

Ikatan pHSA pada virion utuh merangsang terbentuknya antibodi
“anti reseptor pHSA/anti-PAR” yg menahan masuknya HBV ke hepatosit sehat

Proses penghancuran sel-sel hati kompetisi antara sel T sitotoksik

dengan faktor-faktor penghambat
a. “Liver derived inhibitory protein” (LIP) yang dihasilkan oleh hepatosit
b. anti HBc “rosetta inhibiting factor” (SIR) yang dihasilkan oleh limfosit

Akut

sel T sitotoksik berhasil membersihkan hepatosit yang terinfeksi

Kronis

sel T sitotoksik tidak berhasil menghancurkan seluruh hepatosit

yang terinfeksi
Definition of hepatitis B virus, antigens, and antibody
HBV Hepatitis B virus, etiologic agent of serum hepatitis. A hepadnavirus
Hepatitis B surface antigen. Surface antigen of HBV detectable in large
HBsAg
quantity in serum ; several subtype identified
Hepatitis B enveloped antigen. Soluble antigen. A part of the core;
HBeAg related to the potential for infectivity and HBV replication with high titer
of HBV in serum
HBcAg Hepatitis B core antigen
Antibody to hepatitis B surface antigen. Indicates past infection with
Anti-HBsAg and immunity to HBV, presence of passive antibody from HBIg, or
immune response from HBV vaccine
Antibody to hepatitis B enveloped antigen. Presence in serum of
Anti-HBeAg
HBsAg carrier suggests lower titer of HBV
Total antibody to hepatitis core antigen. Indicates infection with HBV at
Anti-HBcAg
some undefined time in the past
IgM class antibody to HBcAg. Indicates recent infection with HBV;
IgM anti-HBcAg
positive for 4-6 months after infection
 ACUTE INFECTION

In those patient, anti-HBc and

Anti-HBs remain present for life,
providing immunity to reinfection

Window period

During the incubation period, HBsAg and HBeAg are the first indicators of HBV infection in the
blood

In some people with acute infections, HBsAg become undetectable before anti-HBs appear.
This is “window period”, during which a person tested for HBsAg and Anti-HBs will appear
uninfected.

Anti HBe and Anti HBs do not appear until the beginning convalescence
CHRONIC INFECTION

The continued presence of HBsAg beyond six months and the absence of
anti-HBs is an indication that infection has become chronic
 Common Serologic Patterns of Hepatitis B Virus Infection
HBsAg HBeAg Anti-HBs Anti-Hbe Anti-HBc Interpretation
+ + - - - Incubation period
Acute HBV infection (typical
+ + - - + (IgM) case); chronic HBV carrier with
high infectivity
- - + - + (IgG) Recovery from HBV infection
Chronic HBV carrier; chronic
+ - - - + (IgG)
hepatitis B
Successful immunization with
- - + - -
HBV vaccine
Applied Therapeutics; ed.20; Koda-Kimble&Young
HBsAg PREVALENCE
 DIAGNOSIS LABORATORIUM

Markers of viral replication:

Serology: HBsAg, HbcAg
HBV DNA (testing with dot blot hybridization/PCR)

Other serology markers:
Anti-HBsAg
IgM anti-HBc
IgG anti-HBc
HBeAg
Anti-HBe
HEPATITIS C
Important properties of Hepatitis C virus (Hepacivirus)

Classification Flaviviridae

Virus Virion 30-60 nm in diameter

Composition RNA
Genome Single-stranded DNA, linier, 9.4 kb in size,
infectious, positive sense
Genomic length transcript produce a
precusor polyprotein encoding nonstructural
Replication and protein (replicase, transcriptase)
Proteins
Subgenomic mRNA encodes struktural
protein
Envelope Two glycoproteins

Variation 6 different genotype, > 90 subtype

 DIAGNOSIS LABORATORIUM …Hepatitis C

SEROLOGY TEST are based on detection of antibodies to recombinant

HCV polypeptide:

Enzyme immunoassay (EIA) measured antibodies directed against
NS4, core, NS3 sequences, and NS5

Recombinant immunoblot assay (RIBA) as a supplemental test

DIRECT DETECTION:

HCV-RNA can be detected in plasma and serum by RT-PCR

Quantity of HCV-RNA

Antigen detection
Detect HCV core antigen in sera by EIA

Genotype (Sequencing of region of the genome)
Based on reverse dot blot hybridization of a PCR amplicon to
nitrocellulose strips coated with genotype-specific probes
HEPATITIS D VIRUS
(DELTA AGENT)
Structure and replication of Hepatitis D virus
Classific Unclassified
ation
Virus Virion 35-37 nm in diameter

Composition RNA

Genome Single-stranded DNA, circular, 1.7

kb in size, negative polarity,
infectious
Replication HDAg is coded by HDV RNA
and Proteins

Envelope An HBsAg envelope surround

delta-antigen
(HD Ag). No homology exits with
HBV genome

HDV requires HBV to serve as a helper virus

for infectious HDV production

HDV RNA genom is replicated and transcribe
in the nucleus by celluler enzym

Hepatitis D virus (HDV) is found in nature only as
coinfection with HBV

Delta antigen (delta-Ag) and antibody (anti-delta)
detected in some HBV infections

Antigen is found within certain HBsAg particles

In blood, HDV contains delta-Ag (HDAg) surrounded by an
HBsAg envelope

Its presence result in more severe acute disease, with
greater risk of fulminant hepatitis, chronically infected
patient, a greater risk of cirrhosis and liver can
Typical Course of Hepatitis C
HEPATITIS E VIRUS

Hepatitis E virus merupakan anggota dari famili Caliciviridae, menunjukkan
sifat-sifat yang sama dengan enterovirus type 72, yakni virus hepatitis A

Endemik di negara-negara tertentu
 Characteristic of Hepatitis Viruses

Virus Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E Hepatitis G

Family Picornaviridae Hepadnaviridae Flaviviridae Ubclassified Caliciviridae Flaviviridae

Genus Hepatovirus Orthohepadnavirus Hepacivirus Deltavirus Unnamed Unnamed

Virion 27 nm, 42 nm, spherical 60 nm, 35 nm, 30-32 nm, 60 nm,

icosahedral spherical spherical icosahedral spherical

Envelope No Yes (HBsAg) Yes Yes (HBsAg) No Yes

Genome ssRNA dsDNA ssRNA ssRNA ssRNA ssRNA

Genome size 7.5 kb 3.2 kb 9,4 kb 1.7 kb 7.6 kb 9.4 kb

Stability Heat and acid Acid stable Ether Acid sensitive Heat stable Ether sensitive
stable sensitive; acid
sensitive
Transmission Fecal-oral Parenteral Parenteral Parenteral Fecal oral Parenteral

Prevalence High High Moderate Low, regional Regional Moderate

Fulminant Rare Rare Rare Frequent In pregnancy ?

disease

Chronic Never Often Often Often Never ?

disease
Oncogenic No Yes Yes ? No ?

Adapted from Jawetz, Melniek, and Adelberg’s Medical Microbiology. 22th edition
 Reference
1. Koziel M.J., Siddiqui A., Hepatitis B Virus and Hepatitis Delta Virus, in: Principles
and Practice of Infectious Disease, 6th ed, Elsevier-Churchill Livingston, p.1864-
1890.
2. Thomas D.L., Ray S.C., Lemon S.M., Hepatitis C, in: Principles and Practice of
Infectious Disease, 6th ed, Elsevier-Churchill Livingston, p.1950-1981.
3. Alter H.J., Hepatitis G and TT Virus, in: Principles and Practice of Infectious
Disease, 6th ed, Elsevier-Churchill Livingston, p.1981-1989.
4. Brooks G.F., Butel J.S., Morse S.A., Hepatitis Viruses, in: Jawetz, Melnick, and
Adelberg’s Medical Microbiology, 22nd ed, Lange-International edition, p. 403-417
5. Mahon C.R., Manuselis G.Jr., Hepatitis Viruses, in: Diagnostic Microbiology,
W.B. Saunders, 1995, p. 812-817.
6. Harvey R.A., Champe P.C., Fisher B.D., Hepatitis B and Hepatitis D (Delta
Viruses), in: Lippincott’s Illustrated Reviews Microbiology, 2nd ed., p. 273-281
TERIMA KASIH