HEPATITIS VIRUS

KURNIA DWI ARTANTI.

DEPT. OF EPIDEMIOLOGY,
FAC. OF PUBLIC HEALTH
AIRLANGGA UNIVERSITY,
SURABAYA
 Introduction
1. Viral Hepatitis is an ancient diseases (5th century BC)
2. MacCallum & Bauer (1947):
- “hepatitis A” for “infectious hepatitis”
- “hepatitis B” for “serum hepatitis”

3. This terminology: adopted by WHO (1973) distinguish 2

infectious agents of hepatitis.

4.. The extensive study (late 20th century): many discoveries:

*. Specific & sensitive serologic test for Hepatitis B virus
(HBV).
*. Pathogenesis and epidemiology of HBV.
*. Development of save and effective vaccine.
*. Additional agent (s): HCV etc.
 Viral Hepatitis: classification
 1. Hepatitis A virus.
 2. Hepatitis B virus
 3. Hepatitis C (1 & 2 & 3 to be discussed).
 4. Hepatitis D virus.
 5. Hepatitis E virus.
 6. Others are Suspected, but not confirm as
human pathogen: GB virus C/hepatitis G,
TT virus (TTV), and SEN virus.
I. Hepatitis A virus (1)
 I. Hepatitis A virus (1)
 A. Clinical Appearance:
◦ a viral infection of liver with very variable
◦ In most patients (90% <5 yrs): an-icteric hepatitis.
◦ In adult: 40 to 70% : shows clinical manifestation.

 The symptoms:
◦ From: mild & transient to severe & prolong
◦ Incubation: from 15 to 50 days, average: 28 days.
◦ Incubation period is inversely correlate with the viral
inoculum size.
◦ Clinical Signs/ Symptoms: not specific
 I. Hepatitis A virus (2)
The symptoms (cont’d):
- Clinical Signs/ Symptoms: not specific
- Short prodromal/pre icteric phase:
several days to > a week.
- Mainly: anorexia, malaise, fatigue, fever,
abdominal pain.
- Less common symptoms: myalgia,
anthralgia, diarrhea, pruritus.
 Epidemiology HAV infection

* Hepatitis A outbreak: first reported about a

century ago.
* Majority affected: 5 to 30 yrs.
* Worldwide: annual incidence: > 1.5
million cases.. Estimate cost: 1.5 to 3
billion US $..
* HAV is endemic, majority are infected (in
developing countries.
 Transmission of HAV

*The mode of HAV transmission: fecal

to oral.
* Poor sanitation and poor personal
hygiene: promote viral transmission.
General Features of Hepatitis A virus

* Belongs to family of Picornaviridae.

 Viral shape: icosahedral.
 No envelope virion, with diameter: 27 to 28 nm.
 Genome: 7,478 nt. With single long ORF.
 ORF ?.
 Positive strand RNA.
 Resistant to environmental stress and stable for a month. Infective
after heating 10-12 hrs at 600C.
 Resistant to ethyl ether and chloroform.
 Inactivation:
 In saline, 4 mnts, 700C
 In saline, immediately at 850C
DIAGNOSIS HAV infection (1)
 Samples:
 Blood for serologic test.
 Feses: HAV antigen, virus.
 First technique used: Immune Electron
Microscopy (IEM): difficult, time
consuming and expensive.
 Serologic test:
 Radioimmunoassay: detect HAV antigen,
early method. Now has been replaced by
ELISA.
 ELISA.
DIAGNOSIS HAV infection (2)
 Molecular Detection:
 Molecular Hybridization technique:
Hybridization of HAV with cDNA of HAV.
 10 fold more sensitive than Immunoassay.
RNA probe
 Dot blot hybridization: HAV-spesific ssRNA
probe.
 RT- PCR.
 For acute HAV infection: assay of anti HAV
IgM: method, solid phase antibody-capture
immuno assay.
Interpretation of (HAV) test result

 Anti HAV IgM: present in serum in

early infection to several months.
Therefore, IgM : indicate recent
infection.
 Total Ig: measure IgM and IgG, IgA
etc.
 IgG positive indefinitely.
 IgG positive, IgM negative ?, has
protection.
 Exogenous IgG ?.
 Transfussion ?.
2. Hepatitis B virus
 Epidemiology HBV infection
* Hepatitis B infection: one of the most common
infectious diseases in the world.
* WHO estimates: >2 billion people infected with
HBV at some time in their live.
* Survey (2000) by WHO: 360 million people
worldwide are carrier of HBV,
- the majority: in Asia and Africa.
* Cause 30% chirrhosis, and ~ 50% Hepatocellular
carcinoma (HCC)
 Epidemiology HBV infection

 ~ 15-40% of infected patients will develop cirrhosis,

liver failure, or hepatocellular carcinoma (HCC).
 HBV infection: .5 to 1.2 mil. Deaths/year.
 the 10th leading cause of death worldwide.
 HCC incidence has increased worldwide, now the 5th
most frequent cancer, killing 300 000-500 000
people/yr
 Hepatitis B virus (1)
 A. Clinical Appearance:
◦ a viral infection of liver with very variable
◦ In most patients: subclinical, No symptoms/ jaundice.
◦ Other patients: symptoms, No jaundice (anicteric
hepatitis)
◦ 25 to 35 %: symptoms with jaundice (icteric hepatitis).

 The symptoms:
◦ From: mild & transient to severe & prolong
◦ Incubation: from 6 wks - 6 months
 Acute Hepatitis B:
◦ Most infant: No Clinical manifestation
◦ 1-5 yrs: 5-10% with Clinical signs
◦ > 5 Yrs /adult: 33- 50% with Clin. Signs
◦ Clinical Signs/ Symptoms: not specific
 Hepatitis B virus (2)
 Clinical Signs/ Symptoms: not specific
*. Symptoms: fatigue, myalgia, anorextia, -
nausea, vomiting.
*. Physical signs:
- jaundice, dark urine, clay color stool,
- hepatomegali.
- Low grade fever (< 39.50C)
*. Lasted: 1 to 2 weeks
*. Icteric: 1 month.
 2. Hepatitis B virus (3)
 The Chronic symptoms:
 Vague and non-specific.
 HBV virion, DNA pol. Activity,
HBV DNA may or may not be
detected.
 Host factor that determine
chronicity / resolution: not known.
Hepatitis B virus (4)
 Chronic Hepatitis B:
 Patients who have HBsAg post. For > 6 moths.
 HBsAg may be produced at high levels even if virus
replication in the liver has virtually ceased. ?
 ..>viral DNA may integrate into host chromosomes
 may be high in
 Likely to remain post. For life (majority).
 About 29%: become neg. after 12 yrs.
 Chronic active: can develop cirrhosis

 Chronic: begins when the immune response that normally

clears the infection fails/too weak:.
 Infections following exposure of children <1 yr or
 Immunocompromized patients
 Transmission of HBV
*. The main mode of HBV transmission: are vertical
(mother to child).
- If the mother is HBe Ag post, the risk of
transmission to infant: 90%.
- If the mother is HBs Ag post., HBe Ag neg. the
rate of transmission: 10%.
*. via sexual activity (homo- and hetero-sex)
 Injection drug use
 Physical contact with infected bodily fluids.
 In some countries in Asia and Africa: the carrier
rate reach as 15%.
 Transmission of HBV
In areas of :
1. high endemicity (Asia and the South Pacific), seroprev. > or
similar to 8%, most infect. are acquired perinatally or
horizontally during childhood.

2. Intermediate endemicity (seroprev. 2-7%, ex: sub-Saharan

Africa, Alaska, the Mediterranean, India): transmitted during
childhood (perinatally/ horizontally) and later in life
(sexually, by intravenous drug use, or by unsafe health care-
related injection practices).

3. Low-prev. regions (most of the developed world, parts of

Central & South America; seroprevalence, < 2%): transmitted
sexually & by intravenous drug use.
General Features of Hepatitis B virus

*. Belongs to family of Hepadnaviridae

 Partially dsDNA virus: 3,200 bp, circular,
overlapping gene.
 Has enveloped
 The complete virus particle: has an outer
envelope, composed of surface antigen
(HBsAg) that surrounds a nucleocapsid or
core.
 Inside core:
 one partially dsDNA
 core protein (HBcAg)
 Hepatitis e antigen (HBeAg)
 Pathogenesis HBV (1)
 Severity of diseases correlates with cellular host
response to infected cells.
 There is no direct correlation between viral load
and severity of liver diseases.
 Recovery of Acute HBV patients dependent on the
vigorous production of antibody to S antigen, and
vigorous CTL response which is polyclonal and
class I restricted, reactive with HBV envelope,
nucleocapsid and polymerase region.
 Pathogenesis HBV (2)

HBV-related liver damage in acute

hepatitis, attribute to mostly to a virus
specific CTL response directed against
hepatocytes infected with HBV.
 There is no clear evidence that that HBV
DNA is oncogenic.
 Multiple factor may contribute to the
cancer development.
 5. Virologi (1)
Classification:
*. HBV:
-. Family: Hepadnaviriday
-…> Hepatotropic DNA Virus.
*.Characteristic of Genome:
- DNA, ca. 3 Kb (3.200 bp).
- Relaxed circular.
- Partially duplex.
 Virologi (2)

*. HBV Virion:
- Envelop (40-42 nm): outer lipoprotein
composed of multiple glycoprotein, mainly
surface antigen (HBsAg)
- Nucleocapsid or core: 180 C-protein,
Icosahedral symetric capsids.
 Inside, core:
◦ one partially dsDNA (genome)
◦ core protein (HBcAg)
◦ Hepatitis e antigen (HBeAg)
◦ DNA polymerase
DIAGNOSIS HBV infection
Serologic test (RIA/ EIA) :
◦ Detect HBV antigens / Antibody
◦ Very sensitive and specific.
Molecular Detection:
◦ Dot blot Hybridization technique:
detect HBV DNA
◦ RNA probe
◦ Amplification DNA using PCR.
Interpretation of test result

 The present of HBsAg: active infection

(acute/chronic)
◦ HBsAg detected: 3 to 5 wks before
symptoms/jaundice.
◦ HBV DNA: 3 to 5 wks before HBsAg serum
 High titer (> 1: 1,000) IgM anti-HBc: acute
infection.
 Chronic Hepatitis: HBeAg, HBV DNA.
 HBeAG post.: more chance to transmit sexually
and perinatally.
 HBV TREATMENT
 No specific treatment for acute HBV:
Symptomatic and supportive.
 Primary goal of treatment: suppress viral
replication, inhibit progression to liver
damage before become cirrhosis.
 Antiviral: Alpha interferon; DNA
analogue.
 PREVENTION

 Avoid: sexual activity with carrier.

 Avoid: body fluid from carrier
 Vaccination.
3. Hepatitis C virus
3. Hepatitis C virus
 Epidemiology:
◦ HCV distributed worldwide, ~ 170 million infected.
◦ Before screening: HCV was the major cause of
transfusion-associated hepatitis.
◦ Seen in USA and France: Infection rate decrease
with blood screening.
◦ Seroprevalence: ~ 3% (worldwide)
◦ Age distribution: most > 15 yrs
 Reinfection: No protective immunity after HCV
infection, ..> in hemophiliac: mixed infection was
detected.
General Features and Genome of HCV

.Virion Morphology
 Filtration and EM: 50 nm, with spike-like
projection.
 Envelope can be extracted with detergent..> core
about 33 nm..
 Genome: plus-strand RNA, 9,500 nt .. > encode
polyprotein 3000 aa.
 Cleavage by host and virus encoded protease,
produse: structural prot. (core) and 2 glycoprotein
E1 and E2) and non-struct. Prot. NS2-NS5.
 General Features and Genome of HCV

 Genome: heterogenous (quasispecies), cause by

RNA pol.
 6 Major genotype, the dominant world-wide are
1,2,3.
 No serotypic classification (not available yet).
 Quasispecies: envade host immune responses.
 Patient with more homogen, more responsive to
interferon.
 HCV: from infection to HCC

Pathogenesis:
◦ Incubation: 6-8 wks.
◦ Exposure to anti HCV can be detected
(by ELISA): 8-9 wks.
◦ HCV RNA detected : 1-2 wks.
◦ Cirrhosis: 20 % of Infection (vary)
◦ HCC: 20-25 % of cirrhosis
◦ Infection to HCC: 10-30 years.
 HCV: from infection to HCC

 Mechanism of HCV infection to cause HCC is

still uknown.
 Reinfection:
◦ Upon infection, the host develop antibodies against
almost all virus antigen.
◦ The first: anti envelop (anti E2) and anti core, at low
concentr.
◦ In chronic (50% of cases) infected patient, antibodies
develop after months or years.
◦ Infection to develope HCC: 10-30 years.
 HCV: from infection to HCC
 Prospective study: post transfussion HCV
◦ 20-50% develop cirrhosis.
◦ 5-25 % develop HCC after 10-30 years
 Retrospective study:
◦ Cirrhosis after 10-15 yrs.
 Other study (in Japan) :
◦ Persistent HCV: cause 70% HCC
◦ Risk to HCC: HCV RNA post 100 X than RNA neg.