Hepatitis B Virus by Dr. Rakesh

1. Hepatitis-B Virus

2. 2
1965 Baruch Samuel Blumberg
Discovered Australia Ag, nowadays known as hepatitis
surface antigen (HBsAg)  while studying human serum
lipoprotein allotypes observed in serum of Australian
aborigine gave line of ppt with sera from 2
hemophiliacs who received multiple blood transfusions.
1970, Dane Cameron and Briggs visualized the
hepatitis B virus (HBV) virion-Dane particle.
Maginus & Espmark  HBe Ag
History

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Family: Hepadnaviridae
Genus: Orthohepadnavirus
Species: Hepatitis B virus
Classification

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• Hepadnaviridae family
• 42 nm DNA virus with an outer envelope and inner core
Morphology

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Hepatitis B surface antigen(S): HBs Ag – the envelope protein –
detectable in blood
Hepatitis B core antigen (HBcAg) – not detectable in blood.
Hepatitis B e antigen (HBeAg) - Detectable in blood during active viral
multiplication, generally at the same time as HBsAg
Antigenic Components

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HBs antigen (HBsAg)
•Specific and first marker for HBV infection to appear in blood.
•Proportion of HBs protein is different in 3 morphological forms
•HBsAg is heterogeneous antigenically, with a common antigen a and
two pair of mutally exclusive antigens d&y and w&r
•Therefore, 4 major subtype adw, ayw, adr and ayr.
Antigen of Hepatitis B

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HBc antigen (HBcAg)
•Derived from envelop that encloses the viral DNA
•Not detectable in the blood stream
•Marker of infectious viral material and accurate index of viral replication
HBe antigen (HBeAg)
•Found in highly productive HBV carriers
•Important in survival & spread of infection

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Nomenclature of Hepatitis B

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•Natural infection occurs only in humans.
• Virus maintained in carriers.
• Largest carrier pool in China followed by India.
• Carrier – a person with detectable HBsAg in blood for more than 6 months.
• Carrier state is more common in males.
• Carriers - two types:
1.Super carriers – high titre HBsAg, along with HBeAg, DNA
polymerase and HBV in circulation, with elevated transaminases.
2.Simple carriers – low infectivity & low titres of HBsAg.
Epidemiology

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•
HBV Modes of Transmission
•Sexual
•Parental
•Perinatal

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Concentration of HBV
in Various Body Fluids
High Moderate Low/Not Detectable
Blood Semen Urine
Serum Vaginal Fluid Feaces
Wound exudates Saliva Sweat
Tears
Breast milk

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IV drug abuse – HBV transmission is Four times more common than HIV
• Transfusion or transplant from infected donor
• Occupational exposure to blood - Mostly needle
sticks
• Iatrogenic – dialysis, unsafe injection practices
(reuse of needles/syringes, contaminated multiple
dose medication vials), dental procedures,
blood bank
Risk Factors Associated with
Transmission of HBV

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•Transmission from Carrier mothers
– by contact of maternal blood with the skin
& mucosa of the fetus during birth
– Very high (60-90%) if the mother is
HBeAg +ve and low (5-15%) if negative
• High risk Sexual behaviour -
Multiple sex partners, homosexuals &
those diagnosed with STDs like HIV,
gonorrhea etc
Risk Factors Associated with
Transmission of HBV

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• Rare but not absent
• Could occur through percutaneous / mucosal
exposures to blood
– Theoretically through sharing of contaminated
personal articles (razors, toothbrushes) –
Contaminated equipment used for home
therapies
► IV therapy
► Injections
Household Transmission of HBV

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Outcome of HBV Infection

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Death
you won't have any
symptoms. Your liver can
still do its job because
there are enough healthy
cells to make up for the
damaged cells and scar
tissue caused by cirrhosis
an acute
deterioration in
liver function in
a patient with
cirrhosis

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Incubation period: long Average 60- 90 days
Range 6 weeks to 6 months
Fever is not prominent
90- 95% with acute hepatitis recover within 1-2 months of
onset.
Mortality in about 0.5-2 % of cases.
1-10% develop chronic infection.
Hepatitis B – Clinical Features

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•Incubation period- 45 to 120 days average 60 to 90 days.
•Phases of disease
1. Preicteric
2. Icteric
3. Convalescent
Acute Hepatitis B

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Preicteric
a. Tiredness
b. Anorexia
c. Vague abdominal discomfort
d. Nausea & Vomiting
e. Sometime arthralgias & rash
Clinical features

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Icteric
a. Within 10days of initial symptoms
b. Dark urine Pale stool Yellowish discoloration of mucous
membranes.
c. Total bilirubin- exceeds 20 to 40 mg/l
d. Hepatospleenomegaly
e. After disappearance of jundice-Anti HBs.

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a. Anti HBc IgM to IgG type
b. Transient presence of HBsAg, HBeAg and viral DNA (<6
months)
c. Seroconversion to anti HBsAg and anti HBeAg
Convalescent

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Acute Hepatitis B Virus Infection with Recovery

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•It may be of two types
•Super carrier
•Highly infectious  very minute amt of serum or blood  transmit the
infection.
•High titer of HBsAg, DNA polymerase.
•Also have HBeAg in blood with elevated ALT.
•Simple carrier
•low titer of HBsAg with negative HBeAg, DNA polymerase.
•can transmit inf  large vol of serum or blood are transfused.
•Types
•Temporary carrier  harbours the HBV for 6 weeks to 6 months.
•Chronic carrier  harbours the HBV for > 6 months
Carriers

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•After acute infection virus remain in 5 to 10% cases of adult, even
more higher among children upto 70 to 90%.
•350 million of person worldwide are chronic carriers. Among them
100 million in China.
•Among the persistent carrier 70% will develop Chronic persistent
hepatitis and remaining 30% will develop Chronic active hepatitis.
Chronic Hepatitis B

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Clinical outcomes of Hepatitis B infection

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•Only 5% patient with cirrhosis develop HCC.
•HCC is responsible for 90% of primary malignant tumor of liver.
•Worldwide 7th most common cancer in male while 9th in female.
•Causes >500000 deaths annually with male & female ratio 4:1.
•Appears after a mean duration of about 35 years of HBV infection.
Hepatocellular carcinoma

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•Rare condition, develop in about 1% cases.
•It is due to massive necrosis of liver substance.
•Usually fatal
•Survival in adult is uncommon.
•Genetic heterogeneity, co-infection, host immunological factors
are responsible.
Fulminant Hepatitis

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Extra-Hepatic Manifestations
•Mediated by circulating immune complexes
•Both acute hepatitis & chronic hepatitis
•Acute hepatitis 10-20%
•Serum sickness like illness
•Fever, rash, artralgia
•Gainotti-Crosti Syndrome (rare skin disease affecting children between the
ages of nine months and nine years. Major symptoms may include blisters on the skin
of the legs, buttocks and arms)
•Glomerular disease

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• Serology – specific diagnosis, demonstration of
serological markers
• HBV DNA levels – indicator of viral replication &
great infectivity- measured by PCR,
DNA:DNA hybridization.
• Histopathology – ground
glass appearance (hazy grey area) of
infected hepatocytes due
to HBsAg.
Laboratory Diagnosis

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Acute Hepatitis B Virus Infection with Recovery

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Interpretation of serological markers

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1. Detection of Viral Markers
a) HBsAg: used as a general marker of infection. Used to document recovery
and/or immunity to HBV infection.
b) HBeAg: indicates active replication of virus and therefore infectiveness.
c) Anti-HBcIgM: marker of acute infection.
d) Anti-HBcIgG: past or chronic infection.
2. Viral DNA Polymerase
3. PCR
4. Biochemical Tests
Laboratory diagnosis

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Concentration of Hepatitis B Virus in
Various Body Fluids
High Moderate Low/Not
detectable
Blood, Serum,
Wound exudates
Semen, Vaginal
Fluid, Saliva
Urine, Feaces,
Sweat, Tears,
Breast Milk

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Clinical Condition Serological Tests
HBs Ag Hbe Ag Anti-HBs Anti-Hbe Anti-HBc
IgM IgG
Late incubation Period or early hepatitis + + - - - -
Acute Hepatitis + + - - + -
Late/chronic HBV infection + +/-* - - - +
Simple Carrier + - - - - +
Super Carrier + + - - - +
Past Infection - - + + - +
Immunity following vaccination - - + - - -
* When +, it indicates high infectivity while – indicates low infectivity

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In Acute viral hepatitis  caused by hepatitis A, B, C, D or E viruses,
transaminase values range between 500 to 2000 units (SGPT is always
higher than SGOT).
Serum bilirubin level  Jaundice  rise upto 25 fold.
Biochemical Tests

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General preventive measures
Health Education
Screening of blood bags, semen donors, organ donors and blood donors
Use of unsterile needles, syringes and other material must be avoided.
Follow safe sex practices by using condoms and avoid multiple sex
partners.
Immunisation
Prophylaxis

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Active Immunisation
Recombinant yeast hepatitis B Vaccine
Produced by recombinant Technology
Plasmid containing gene of HBsAg has been incorporated
Is immunogenic, safe and free from side effects.
Dose: 1.0 mL at 0,1,6 months  administered I.M.
Vaccinated person is protected if they have anti-HBsAg Ab titre of ≥10IU/mL
Immunisation

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HBIG is prepared from donors with high titres of anti-HBs.
Dose: 0.06mL/Kg (or 10-12 IU/Kg)  I.M.
Should be administered as early as possible after exposure  ideally within
hours, but not later than 7 days.
Provides temporary but immediate production.
Indications
Accidental percutaneous or permucosal exposure to HBsAg positive blood.
Infant born to HBsAg positive mother.
Sexual contact of an HBsAg positive person.
Protection against HBV infection after liver transplantation.
Passive Immunisation

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Recommended to neonates born to HBsAg positive mothers.
HBIG 0.5mL  I.M. after birth followed by full course of hepatitis
B vaccine.
1st dose given within 12 hrs of birth.
Combined Vaccination

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Belongs to family Flaviviridae.
Morphology
50-60nm virus
Linear SSRNA
Surrounded by envelope carrying glycoprotein spikes.
Hepatitis C Virus (HCV)

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•
HCV Modes of Transmission
•Sexual
•Parental
•Perinatal

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I.P.  15-160 days, average 50 days.
75% infections are subclinical.
Generally less severe with milder symptoms, absent or less
marked Jaundice.
50-80% develop  chronic hepatitis.
Persistent presence of virus in blood  cirrhosis and
hepatocellular carcinoma.
Clinical Features

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Detection of Anti-HCV Ab
Recombinant Immunoblot Assay (RIBA)
HCV core Ag Assay
RT-PCR
Prophylaxis (General Preventive measures of HepB)
Laboratory Diagnosis

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Hepatitis D, E and G
Self Study

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A
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The first stage is immune tolerance.
•The duration of this stage for healthy adults is approximately 2-4 weeks and
coincide with the incubation period. For newborns, the duration of this period
often is decades.
•Active viral replication is known to continue despite little or no elevation in the
aminotransferase levels and no symptoms of illness.
•In the second stage, an inflammatory reaction with a cytopathic effect occurs.
•HBeAg can be identified in the sera and a decline of the levels of HBV DNA is
seen.
Four stages in the disease

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•The duration of this stage for patients with acute infection is approximately 3-4
weeks (symptomatic period).
•For patients with chronic infection, 10 years or more may elapse before
cirrhosis develops.
•In the third stage, the host can target the infected hepatocytes and the HBV
Viral replication no longer occurs.
•HBeAb can be detected. The HBV DNA levels are lower or undetectable, and
aminotransferase levels are within the reference range.
•In this stage, an integration of the viral genome into the host's hepatocyte
genome takes place.
•HBsAg still is present.

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•In the fourth stage, the virus cannot be detected and antibodies to
various viral antigens have been produced.
•Different factors have been postulated to influence the evolution of
these stages, including age, sex, immunosuppression, and co-infection
with other viruses.
Ad

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High-replicative(super carrier)
•HBsAg, HBeAg and HBV DNA present and detectable in sera.
•ALT may increase
•Moderate inflammatory activity
•Histologically apparent
•Risk of developing cirrhosis is high.
Phases of viral replication in chronic Hepatitis B

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Low-replicative
•Loss of HBeAg
•Decreased HBV DNA concentration
•Appearance of Anti HBeAg
•Decreased inflammatory activity
Non-replicative
•Viral markers are absent or below detectable level.
•Diminished inflammatory activity
•If cirrhrosis already then persist indefinitely.

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A
Hepatitis D Virus