2. 2
What is Viral Hepatitis ?
• Viral hepatitis is a systemic
disease with primary
inflammation of the liver by any
one of a heterogenous group of
hepatotropic viruses
(A,B,C,D,E,G)
3. 3
HEPATITIS VIRUSES
• Hepatitis A (HAV) Picornaviridae (1973)
• Hepatitis B (HBV) Hepadnaviridae (1970)
• Hepatitis C (HCV) Flaviviridae (1988)
• Hepatitis D (HDV) ? (1977)
• Hepatitis E (HEV) (Caliciviridae) (1983),
Hepeviridae
• Hepatitis F – Not separate entity – Mutant of B
Virus.
• Hepatitis G (HGV) Flaviviridae (1995)
4. 4
Viral Hepatitis - Historical
Perspectives
“Infectious” AA
Viral hepatitis NA:NBNA:NB
E
Enterically
transmitted
“Serum” B D C
Parenterally
transmitted
F- Mutant
Of B
G
5. 5
Type of Hepatitis
A B C D E
Source of
virus
Feces Blood
Blood derived
Body fluids
Blood
Blood derived
Body fluids
Blood
Blood derived
Body fluids
Feces
Route of
Transmission
Feco-oral Percutaneous
Permucosal
Percutaneous
Permucosal
Percutaneous
Permucosal
Feco-
oral
Chronic
Infection
No Yes Yes Yes No
Prevention Pre Post
Exposure
Immunization
Pre Post
Exposure
Immunization
Blood donor
screening
Blood donor
screening
Pre Post
Exposure
Immunization
Ensure
Safe
Drinking
water
7. 7
Hepatitis A Virus
CLINICL FEATURES: Majority is asymptomatic.Overt illness is seen only in
5%.
INCUBATION PERIOD: 2-6 WEEKS
Consist of 2 stages- PRODORMAL or PERICTERIC STAGE
ICTERIC STAGE
COMMON SYMPTOMS: Fever, malaise, anorexia, vomiting and liver
tinderness
RECOVERY: 4-6 WEEKS
•The disease is milder in children, in whom many infections may be
Anicteric.
•Mortality is low (0.1-1%) , with most of the death occuring in Adults.
•It was 1st
demonstrated by Feinstone et al.(1973) using Immuno Electron
Microscopy.
MORPHOLOGY: length is 27 nm,non-enveloped RNA virus, belong to family
piconavirus and was designated as ENTEROVIRUS 72. It is now recognised
as the prototype of a new genus Hepatovirus.
8. 8
RESISTANCE ( HAV)
• Resistant to inactivation by heat at 600
C for one hour, ether & acid at
pH 3.
• Inactivated by boiling for one minute, 1: 4,000 formaldehyde at 370
C
for 72 hours & chlorine 1 ppm for 30 minutes.
• Not affected by anionic detergents.
• Survives prolonged storage at 40
C or below.
Hepatitis A Virus Transmission
• Close personal contact
(e.g., household contact, sex contact, child day care
centers)
• Contaminated food, water
(e.g., infected food handlers, raw shellfish)
• Blood exposure (rare)
(e.g., injecting drug use, transfusion)
9. 9
Prodromal or Preicteric phase :
(symptoms: fatigue, joint- and
abdominal pain, malaise,
vomiting, lack of appetite,
hepatomegaly)
Icteric phase: Icterus: jaundice (skin,
sclera, mucous membranes,
cause: elevated bilirubin level,
bilirubinuria: dark urine, pale stool)
10. 10
EPIDEMIOLOGY
• Natural infection is seen only in humans.It is
transmitted by the fecal oral route.Infection is by
ingestion.Virus multiplies in the intestinal epithelium
and reaches to the liver through hematogenous
spread.Once jaundice develops it is rarely detectable
in feces.
• A brief viremia occurs in the preicteric stage but
ceases with the onset of jaundice.
• Parenteral transmission is very rare.
• HAV may br present in the saliva and urine of patients
but its not a factor for their transmission.
• The epidemiology of type A virus resembles that of
poliomyelitis.
• In India it is the most commom cause of acute
hepatitis in children and mostly occurs during rain.
11. 11
LAB.DIAGNOSIS
• Demonstration of Virus in feces:
• By: Immunoelectron microscopy
• Virus Isolation:
• Detection of Antibody :By ELISA
• Biochemical tests:
• i) Alanine aminotransferase (ALT)
• ii) Bilirubin
• iii) Protein
• Molecular Diagnosis : RT PCR of feces
12. PROPHYLAXIS
• GENERAL: It consist of improved sanitary practices and
prevention of fecal contamination of food and water. A safe
and effective formaline inactivated and alum conjugaged
vaccine containing HAV grown in human diploid cell is
available that can be taken as a full course . Protection
begins 4 weeks after injection.
• SPECIFIC PASSIVE: It is by pooled normal human
immunoglobulin(16% solution in a dose of 0.2-0.12mL/kg
body weight)IM brfore exposure can prevent the illness.
12
14. 14
HBV : Structure
• Virion also referred to as Dane particle (ds-tranded
DNA)
• 42nm enveloped virus
• Core antigens located in the center (nucleocapsid)
* Core antigen (HBcAg)
* e antigen (HBeAg)- an indicator of
transmissibility (minor component of the core-
antigenically distinct from HBcAg)
• 22nm spheres and filaments other forms- no DNA in
these forms so they are not infectious (composed
of surface antigen)- these forms outnumber the
actual virions.
15. 15
HBV Structure & Antigens
Dane particleDane particle
HBsAg = surface (coat) protein ( 4 phenotypes : adw, adr, ayw and ayr)
HBcAg = inner core protein (a single serotype)
HBeAg = secreted protein; function unknown
16. Clinical Features
Incubation period: Average 60-90 days
Range 45-180 days
Insidious onset of symptoms.
Tends to cause a more severe disease than Hepatitis
Clinical illness (jaundice): <5 yrs, <10%
≥ 5 yrs, 30%-50%
1/3 adults-no symptoms
Clinical Illness at presentation 10 - 15%
Acute case-fatality rate: 0.5%-1%
Chronic infection: < 5 yrs, 30%-90%
≥ 5 yrs, 2%-10%
More likely in asymptomatic
infections
Premature mortality from
chronic liver disease: 15%-25%
16
17. ANTIGENIC DIVERSITY
• HBsAg contains 2 different antigenic components-Ag a
& 2 pairs of specific Ag dy and wr,only one member
being present at a single time. SUBTYPES-
adw,adr,ayw,ayr. The subtypes are not important in
immunity because the dominant Ag a shared by all.
• HBcAg : Mild detergent treatment disrupts the viral
envelope and exposes the core.The Ag expressed in
the core is called hepatitis B core Ag.
• HBeAg : It is a soluble non particulate nucleocapsid protein.
• VIRAL GENOME:
• The genome has 4 overlapping genes;
• S gene codes for surface Ag.Consists of 2 regions i.e S & 2
pre-S regions.Protein coded by the S region is called Major
protein.When translation of the begins from the pre-S2 region,
major ptotein is formed and whem the entire gene
18. from the pre-S1 is translated, the L protein is formed.
• The C gene has 2 regions-C and pre-C. When C region
alone is translated the core Ag (HBcAg) is formed. It is not
circulated in the blood but can be demonstrated by
immunofluorescence. If translation begins from pre-C
region, the resulting protein is HBeAg. Presence of HBeAg
in the blood provides a convenient detectable marker of
HBV replication.
• The P gene is the largest and codes for the DNA
polymerase enzyme.
• The X gene codes for a small nonparticulate protein
(HBxAg), that has transactivating effects on both viral and
some cellular genes.
20. • Parenteral - IV drug abusers, health workers are at
increased risk.
• Sexual - sex workers and homosexuals are particular
at risk.
• Perinatal (Vertical) – mother (HBeAg+) →infant.
RESISTANCE:
Heat stable virus. Susceptible to chemical agents.
Exposure to hypochlorite or 2% glutaraldehyde
inactivates the infectivity.
EPIDEMIOLOGY:
It occurs all over the world. The virus is maintained in
the large pool of carriers whose blood contains
circulating HBsAg virus.
HBV:HBV: Modes of TransmissionModes of Transmission
21. Carriers are of 2 categories:
• SUPER CARRIERS:Highly infectious and having
high titre of HBsAg along with HBeAg. Some of
them have high antigenemia and viremia, upto
10^13 HBsAg particles.
• SIMPLE CARRIERS: They have low infectivity
and low titre HBsAg with –ve HBeAg.
High-risk groups for HBV infection
• 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 21
22. 22
Pathogenesis & Immunity
• Virus enters hepatocytes via blood
• Immune response (cytotoxic T cell) to viral
antigens expressed on hepatocyte cell surface
responsible for clinical syndrome
• 5 % become chronic carriers (HBsAg> 6 months)
• Higher rate of hepatocellular ca in chronic
carriers, especially those who are “e” antigen
positive
• Hepatitis B surface antibody likely confers
lifelong immunity (IgG anti-HBs)
• Hepatitis B e Ab indicates low transmissibility
23. 23
Possible Outcomes of HBV InfectionPossible Outcomes of HBV Infection
Acute hepatitis B infection
Chronic HBV infection
3-5% of adult-
acquired infections
95% of infant-
acquired infections
Cirrhosis
Chronic hepatitis
12-25% in 5 years
Liver failureHepatocellular
carcinoma
Liver transplant
6-15% in 5 years 20-23% in 5 years
DeathDeath
24. 24
Diagnosis
• A battery of serological tests are used for the diagnosis of acute
and chronic hepatitis B infection.
• HBsAg - used as a general marker of infection, bcoz it remains
throughout the icteric phase.It disappears after about 2 months of
clinical disease. After its disappearance. Its Ab i.e. anti HBs
appears and remains for a long period of time.
• HBcAg – Its not seen in circulation. Enclosed within the HBsAg
coat. Its Ab anti-HBc appears in the serum after few weeks. It’s
the earliest Ab marker to be seen in blood before anti-Hbe or anti-
HBs. Its remain for lifetime. Selectively anti-HBc is IgM but later
converted to IgG.
• HBeAg- it appears in the blood along with HBsAg. Its an indication
of active intrahepatic viral replication, presence of DNA
polymerse,HBV DNA and virions that indicates high infectivity.
Disappearance of transaminase level in blood indicates Anri-HBe
25. Prophylaxis and immunisation
Avoiding promiscuous sex,drugs,direct & indirect contact with
blood, semen & other body fluids.
IMMUNISATION : Passive, Active & Combined
PASSIVE : HBIG(hyper immune hepatitis immuno globulin) with
anti-HBs is administered into patients after infections with a
dose of 300-400 intra muscularly.
ACTIVE : A special vaccine containing all antigenic components
of HBsAg i.e. pre-S1,pre-S2 & s gene is administred which
gives greater seroconversion. Its last for a longer period of time.
COMBINED : For babies born to carrier mothers, a single injection
of 0.5mL HBIG given IM after birth. And followed by full course
vaccine. 1st
dose being given within 12 hrs of birth.
TREATMENT : No specific antiviral treatrment is available.
Interferon alpha alone or in combination with antiviral agents
such as Lamivudine & Famcyclovir may be given.
25
27. Hepatitis C - Clinical Features
• Incubation period:15-160 days, Mean-50 days.
• Clinical illness (jaundice):30-40% (20-30%) people
• Chronic hepatitis: 50-80% patients
• Persistent infection: 85-100%
MORPHOLOGY :
Can be cloned in E.coli, 50-60nm in size, linear ss RNA
genome enclosed within a core & sorrounded by an
envelope carrying glycoproteins spikes. Resembles
flavivirus in str. & organisation. & hs been clasified as a
new new genus Hepacivirus in the family Flaviviridae.
Atleast 6 different genotypes and many subtypes have been
identified indicating high mutability.Some are locaised &
some are worldwide. 27
28. 28
HCV replicates exclusively in the cytoplasm
via an RNA intermediate
Nucleus
Viral entry & uncoating
Translation & processing
(+)
(+)
(-)
(+)
HCV RNA
replicationVirus particle
assembly Replicative
intermediate
29. • LAB DIAGNOSIS:
Standard method is by ELISA. AG used are structural and
non structural proteins cloned E.coli. 3 successive
generation areare introduced to improve sensitivity and
specificity of serological diagnosis. 3rd
generation ELISA
employs NS-5 region protein & synthetic peptides & it
shows +ve reactions . Confirmation by immunoblot assay
is recommended.
In HCV infection culture Ab appears irregularly & therefore
not easily diagnosised. And culture is not yet established.
Molecular methods like PCR & branched DNA assay are
employed.
29
30. 30
Transfusion or transplant from infected donor
Injecting drug use
Hemodialysis (yrs on treatment)
Accidental injuries with needles/sharps
Sexual/household exposure to anti-HCV-positive contact
Multiple sex partners
Birth to HCV-infected mother
Risk Factors Associated with Transmission of
HCV
31. 31
Treatment
• Interferon - may be considered for patients with chronic active
hepatitis. The response rate is around 50% but 50% of
responders will relapse upon withdrawal of treatment.
• Ribavirin - there is less experience with ribavirin than
interferon. However, recent studies suggest that a combination
of interferon and ribavirin is more effective than interferon
alone.
EPIDEMIOLOGY
It seen only in humans. Source of infections are large no. of
carriers. Infection is mainly by blood transfusion and others
mode of contact by infected blood.
34. 34
Hepatitis Delta Virion(HDV)
From Murray et. al., Medical
Microbiology 5th
edition, 2005,
Chapter 66, published by Mosby
Philadelphia,,
Figure 66-14
35. 35
HEPATITIS D VIRUS
(HDV, DELTA AGENT)
VIRION: spherical,
36-38 nm,
HBV capsid, HDV
nucleoprotein
NUCLEIC ACID: (-)
ss RNA, circular
Satellite virus :
replicates only
in the presence of
HBV
36. 36
Hepatitis D Virus
• The delta agent is a defective virus which shows
similarities with the viroids in plants.
• The agent consists of a particle 35 nm in diameter
consisting of the delta antigen surrounded by an outer
coat of HBsAg.
• The genome of the virus is very small and consists of a
single-stranded RNA.
37. 37
The HDV genome
Figure 88-4 Structure of the HDV RNA Genome. The single-stranded circular RNA genome is indicated by the
heavy black continuous line. The genome has the ability to form an unbranched rod structure, in which
approximately 70% of the bases are engaged in Watson-Crick pairs with counterparts from the opposite side of the
circular RNA. In this unbranched rod structure, the region encoding HDAg (nt 1598-957) is on one side. The RNA
editing site is at position 1012 in the antigenome. The region on the right-hand side contains the autocatalytic
cleavage sites (ribozymes), one in the genome (nt 686) and the other in the antigenome (nt 900). The genome binds
HDAg and is transcribed by a host DNA–dependent RNA polymerase.
Fields Virology 4th
edition, 2002, Chapter 88, Lippincott, Williams and Wilkins, 2002 Fig. 88-4
38. 38
• Coinfection :severe acute disease.Low risk of chronic
infection.
• Superinfection :usually develop chronic HDV infection.
High risk of severe chronic liver disease.May present as
an acute hepatitis.
Hepatitis D Virus Modes of Transmission
• Percutaneous exposures
• injecting drug use
• Permucosal exposures
• sex contact
Hepatitis D - Clinical Features
39. LABORATORY DIAGNOSIS
The delta Ag is primarily expressed in liver cell nuclei & there it
can b demonstrated by immunofluorescence. Occassionaly
present in serum. Through ELISA anti-D can be detected in
the serum. IgM Ab appears after 2-3 weeks of infection & is
replaced by IgG. In chronic infection IgM remains for long
time. Delta RNA sequences & DNA probes are used rapid
identification.
Hepatitis D – Prevention
• HBV-HDV Coinfection
Pre or post exposure prophylaxis to prevent HBV infection.
• HBV-HDV Superinfection
Education to reduce risk behaviors among persons with
chronic HBV infection.
39
41. 41
TYPE E HEPATITIS
(Enterically transmitted NANB or Epidemic NANB Hepatitis)
• Calicivirus-like viruses
• unenveloped RNA virus, 32-34nm in diameter
• +ve stranded RNA genome, 7.6 kb in size.
• very labile and sensitive
• Can only be cultured recently
It is named so as because it is transmitted enterically
through fecal pollution of drinking water in many
developing countries.
Previously it was mistaken by hepatitis A bcoz of clinical
and epidemiological similarities. It was recognized as
separate due to the absence of Serological & virological
evidenceof HAV infection in these case.
Source of infection is mainly fecal contaminated drinking
water.
42. 42
Incubation period: Average 40 days
Range 15-60 days
Case-fatality rate: Overall, 1%-3%
Pregnant women,
15%-25%
Illness severity: Increased with age
Chronic sequelae: None identified
Hepatitis E - Clinical Features
43. 43
• Most outbreaks associated with faecally contaminated drinking
water.
• Several other large epidemics have occurred since in the Indian
subcontinent and the USSR, China, Africa and Mexico.
• In the United States and other nonendemic areas, where outbreaks of
hepatitis E have not been documented to occur, a low prevalence of
anti-HEV (<2%) has been found in healthy populations. The source
of infection for these persons is unknown.
• Minimal person-to-person transmission.
LAB. DIAGNOSIS
HEV can be demonstrated by IEM(Immuno e- Microscopy) in the bile
& feces of patients during the incubated period. Invitro cultivation is
not successful so far. ELISA kits are also available for IgG & IgM
Abs. using synthetic Ags.
Epidemiology
44. 44
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
Prevention and Control Measures for
Travelers to HEV-Endemic Regions
45. HEPATITIS G VIRUS
GB virus C(GBV-C), formerly known as HGV is a
virus in th family Flaviviridae. & a member of the
genus Pegivirus. These are RNA virus identified
during 1995 & were found to be 2 isolates of the
same virus. It is named after surgeon G. Barker
who fell in non A non B hepatitis which was thought
to be a new hepatic virus.
It is phylogenitically related to HCV.GBA-A & GBV-B
infects tamarin monkeys while GBV-C infects
humans.
About 10-25% hepattits C infected patients & 14-36%
drug users who are sero+ve shw the evidence of
GBV-C infection. 45
46. • It has been clasified into 6 genotypes any many
subtypes with different geographical distributions.
• Genotype 1 is of 5 subtypes and found in Africa.
• Genotype 2 in europe & 3 is most commpon in
Asia.
• It has ssRNA genome of sixe 9.3kb & contains
sinle ORF(open reading frames). Encoding 2
structural (E1&E2) & 5
nonstructural(NS2,NS3,NS4,NS5A,NS5B) proteins
.
46
