VIRAL HEPATITIS

INTRODUCTION

Viral Hepatitis is the preventable public health problem in

India.
Acute infection with the hepatitis virus may results in
conditions ranging from sub-clinical disease to selflimited symptomatic disease to fulminant hepatic failure.
Adults with hepatitis A or B are usually symptomatic and
with hepatitis C are either symptomatic or asymptomatic.
It is responsible for more than 90% cases of both acute
and chronic hepatitis
Types A and E cause only acute hepatitis and spread by
faecal-oral route
Types B,C,D and G cause both acute & chronic hepatitis
and are transmitted by blood and blood products and
body fluids

Types and causes of viral hepatitis

Acute Hepatitis - Causes

Hepatitis A virus
Hepatitis B virus
Hepatitis C virus
Hepatitis D virus
Hepatitis E virus
Hepatitis G virus
Cytomegalo, Epstein-Barr,
Herpes Simplex, Yellow
Fever viruses
TT virus (new)

Chronic Hepatitis -Causes

Hepatitis B virus
Hepatitis C virus
Hepatitis D virus
Hepatitis G virus

History of viral hepatitis

8th Century

: Infectious Nature of HBV suggested

17th-19th Centuries: Outbreaks of epidemics of jaundice

1883
1908
1939-1945

in military and civilian populations

during wars
: Lurman reports outbreaks of serum
hepatitis following vaccination of docters
: McDonald postulates that the infectious
jaundice is caused by a virus
: WWII-A series of outbreaks after
vaccination for measles and yellow fever

1947 : Mac Callum classifies viral hepatitis into two

typesViral hepatitis A---> Infectious hepatitis

Viral hepatitis B---> Serum hepatitis
1965: Blumberg discovers Australia antigen (HBsAg) in
aborigines and shows presence of antigen at high
frequency in patients with leukaemia and children with
Down's syndrome
1970: Dane discovers the Dane particle (complete HBV
particle)
1972: Discovers HBeAg
1973: Feinstone and Purcell identifies HAV

1977: Rizzetto describes delta antigen HDV

1983: Recovery of HEV
1988: Chiron group (Choo, Kuo, Houghton) closes and

identifies HCV.
1995: Abbot group reports GB Virus-C (GBV-C) and
Genelabs group reports in 1996 hepatitis
1996: Chang's group at NTUH reports in JAMA the
successful prevention of HBV infection by nation-wide
vaccination on new born babies launched in 1984 in
Taiwan.
1997: Chang's group at NTUH reports in NEJM a
decrease in annual incidence rate of hepatocellular
carcinoma in children ascribed to nation-wide vaccination
against HBV on newborn babies launched in 1984 in
Taiwan.

Viral Hepatitis- Historical perspectives

INFECTIOUS
ENTRICALLY

VIRAL HEPATITIS

SERUM
PARENTALLY

NANB

F,

HEPATITIS A

The causative agent is

hepatitis A virus (HAV)

Family Picornaviridae; genus
Hepatovirus
Prevalence of HAV is inversely
proportional to the socioeconomic class
Major public health problem,
1.4 million cases reported each
year worldwide.
In developing countries,
pediatric disease and in
developed countries, disease
of adults.

DISTRIBUTION- Worldwide
Approximately 1.4 million cases reported every year
In USA, reported cases ( American Academy of Paediatrics)

1981

57,929 (45% HAV)

1990

31,441

1995

31,582

HAV is the most common of the acute hepatitis in United States.

In Shinghai (China), 300,000 cases of hepatitis A and 32 deaths (

attack rate of 4083/100,000 population) were reported in 1988.

Problems in India
100,000 cases of viral hepatitis per annum are being

reported.
Initially HAV was know as the infectious or epidemic
hepatitis virus because of its typical association with
epidemics caused by contaminated water and food
worldwide.
Mortality : less than 1%
Morbidity : Patient feel ill and confined to bed up to 6
weeks and severity depends upon the nutritional status
and immunodeficiency and the general state of health.

Immunity
One attack confers life long immunity.
Developed countries- 95% Immunity.
Developing countries- less than 50%.

Resistance
HAV-highly infectious and epidemic.
Resistant to unfavourable environmental conditions(water

treatment and disinfection process)

0.5 mg/l of residual chlorine ensure safety against HAV.

Mode of transmission:
Close personal contact

(e.g., household contact, sex contact, child day care

centres)
Contaminated food, water
(e.g., infected food handlers, raw shellfish)
Blood exposure (rare)
(e.g., injecting drug use, transfusion)

Hepatitis A - Clinical Features

Incubation period:

Average 30 days
(Range 15-50 days)
Jaundice by
<6 yrs : <10%
age group:
6-14 yrs : 40%-50%
>14 yrs : 70%-80%
Complications:
Fulminant hepatitis
Cholestatic hepatitis
Relapsing hepatitis
Chronic sequelae:
None
15% of people infected with HAV will have prolonged or
relapsing symptoms over a 6-9 month period.

Laboratory diagnosis
Acute infection is

diagnosed by the detection

of HAV-IgM in serum by
EIA (detectable within 5-10
days after the onset of
symptoms and persisting
for up to 6 months after
infection)
Past Infection i.e. immunity
is determined by the
detection of HAV-IgG by
EIA.

Hepatitis A Vaccination Strategies

Epidemiologic Considerations
Many cases occur in community-wide outbreaks
No risk factor identified for most cases
Highest attack rates in 5-14 year olds
Children serve as reservoir of infection
Persons at increased risk of infection
Traveller's
Homosexual men
Injecting drug users

Vaccination
Inactivated and live attenuated vaccines

against HAV are available.

India do not have definite policies for hepatitis
A vaccination.

Prevention
Proper Hygiene
Sanitation ( clean water source)
Hepatitis A vaccine ( pre and post exposure)
Immunoglobulin (pre and post exposure)

Pre-Exposure
Interventions
Vaccine is recommended for
children under 19 years of age
Travels to countries with high rates of hepatitis A
Drug users
MSM
Immunoglobulin recommended for
Travelers to countries with high rates of hepatitis S who

are leaving in <2 weeks

Post-Exposure Intervention
(within 14 days)
Immunoglobulin
Household and other intimate contacts
Vaccination:
common source exposure (e.g., food prepared by

infected food handler

institutions (e.g., day care centers)

Hepatitis B

The causative agent is

hepatitis B virus (HBV)

Earlier referred as Serum
Hepatitis.
200-fold higher risk of
primary hepatocellular
carcinoma

Properties of HBV:
A member of the hepadnavirus group
Circular partially double-stranded DNA viruses
Replication involves a reverse transcriptase.
endemic in the human population and hyperendemic in many
parts of the world.
a number of variants
It has not yet been possible to propagate the virus in cell culture
Carrier state :
10% of infants and up to 30% of adults infected by HBV.
90% of infants , 30% of 1-5 yrs childrens and 6% of adults
infected with HBV develop chronic infection.
Chronic carriers can infect others and they are prone to cirrhosis
and hepatic carcinoma

 Virion also referred to as Dane

Structure-HBV

particle (ds-stranded 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 coreantigenically 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

Genome

There are 4 open reading

frames derived from the same

strand (the incomplete + strand)
S - the 3 polypeptides of the
surface antigen (preS1, preS2
and S - produced from
alternative translation start sites.
C - the core protein
P - the polymerase
X - a trans-activator of viral
transcription (and cellular
genes?). HBx is conserved in all
mammalian (but not avian)
hepadnaviruses. Though not
essential in transfected cells, it
is required for infection in vivo.

HBV Replication:

Reverse transcription: one

of the mRNAs is replicated

with a reverse transcriptase
making the DNA that will
eventually be the core of the
progeny virion
RNA intermediate: HBV
replicates through an RNA
intermediate and produces
and release antigenic decoy
particles.
Integration: Some DNA
integrates into host genome
causing carrier state

Epidemiology

350,000,000 carriers worldwide

120,000,000 carriers in China
- the carrier rate can exceed 10%
-15 to 25% of chronically infected patients will die from chronic

liver disease
982,297 liver disease in China 2005
50% of children born to mothers with chronic HBV in the US are
Asian American
Problem:
Highly endemic areas are those where HBsAg prevalence is
>10%
Medium endemicity means prevalence between 2 to 10%. India
falls in this zone
Low endemicity means prevalence less than 2 %

Global Patterns of Chronic HBV Infections

High (>10%): 45% of global population

lifetime risk of infection >60%
early childhood infections common
Intermediate (2%-10%): 43% of global
population
lifetime risk of infection 20%-60%
infections occur in all age groups
Low (<2%): 12% of global population
lifetime risk of infection <20%
most infections occur in adult risk groups

High risk groups

People from endemic regions
Babies of mothers with chronic HBV
Intravenous drug abusers
People with multiple sex partners
Haemophiliac's 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

Pathogenicity and 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 carcinoma 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

Concentration of Hepatitis B Virus

in Various Body Fluids
High

Moderate

blood
serum
wound exudates

semen
vaginal fluid
saliva

Low/Not
Detectable
urine
feces
sweat
tears
breast milk

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 A.
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:
15%-16%
Chronic infection:
< 5 yrs: 30%-90%
5 yrs: 2%-10%
Premature mortality from
chronic liver disease:
15%-25%

Laboratory 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.
HBsAb - used to document recovery and/or immunity to HBV
infection.
anti-HBc IgM - marker of acute infection.
anti-HBcIgG - past or chronic infection.
HBeAg - indicates active replication of virus and therefore
infectiveness.
Anti-Hbe - virus no longer replicating. However, the patient can still
be positive for HBsAg which is made by integrated HBV.
HBV-DNA - indicates active replication of virus, more accurate than
HBeAg especially in cases of escape mutants. Used mainly for
monitoring response to therapy.

Prevention
Vaccination
- highly effective recombinant vaccines
Hepatitis B Immunoglobulin (HBIG)
-exposed within 48 hours of the incident/ neonates whose
mothers are HBsAg and HBeAg positive.
Other measures
-screening of blood donors, blood and body fluid precautions.

Vaccinate high risk adults:

Healthcare workers
IV drug users
Household contacts of people w/ Hep B
Patients with multiple sexual partners
Men who have sex with men
HD patients
Patients who require repeated transfusions of blood
products
Patients with chronic liver disease

Hepatitis B vaccination
Infants: several options that
depend on status of the mother
If mother HBsAg negative:
birth, 1-2m,6-18m
If mother HBsAg positive:
vaccine and Hep B immune
globulin within 12 hours of
birth, 1-2m, <6m
Adults
* 0,1, 6 months
Vaccine recommended in
All those aged 0-18
Those at high risk

Vaccine efficacy

Positive immune response is

defined as development of
anti-HBs at a titre of >10 IU/L
95% sero-conversion in
healthy adults
Post-vaccination testing in
healthcare workers/HD pts/pts
who are at risk for recurrent
exposure 1-2 months after
completion of vaccination.
Non-responders complete a
second 3-dose vaccination
series

Hepatitis C
Hepatitis C is caused

by infection with the

hepatitis C virus (HCV),
an enveloped, single
stranded, positive
sense RNA virus.
Earlier known as posttransfusion non A-non
B hepatitis.
Belongs to family
Flaviviridae

Features of Hepatitis C
Salient Features of HCV infection
12-25% sporadic cases
Asymptomatic in 50% of cases
Undetected up to 10 years
20% fully recover in 6 months
5% chronic cases have increased chance of

liver carcinoma.
Prevention

Epidemiology
3% of world population is infected with HCV.
170 million individuals are chronic carriers at risk of
developing liver cirrhosis and liver cancer.
Over 50% of cases are asymptomatic.
Most common cause of chronic hepatitis

INCUBATION PERIOD : 6-7 weeks (range: 2-26 weeks);

CLINICAL FEATURES :
1. Acute HCV infection is often silent, but
2. if evident then diagnosed when there is
circumstantial evidence for new infection,such as a
recent exposure to a known HCV-infected person or
clinical features of acute hepatitis (jaundice, nausea,
anorexia, and malaise) with the exclusion of other
causes of hepatitis.
3. Acute hepatitis C rarely causes fulminant hepatic
failure.

LONG-TERM EFFECTS :
1.50-85% with HCV develop chronic infection,
2.15- 50% of newly infected clear the virus
spontaneously.
3.10-15% with chronic HCV infection develop
progressive fibrosis of the liver leading to cirrhosis.
4. Hepatocellular carcinoma (HCC) risk is about 1-4% /
year.
5. Deaths from chronic liver disease: 1%-5%

TRANSMISSION :HCV is transmitted primarily by :

Direct percutaneous exposures to infectious blood,
such as through injection drug use
Transfusion of contaminated blood products
Inefficiently transmitted through sexual contact
persons with multiple sexual partners
Mother to child in approximately 5-6% of pregnant
women who have chronic HCV infection at the time of
delivery.
Tattooing with contaminated needles
HCV is not spread by kissing, sneezing, hugging,
coughing, food or water, sharing eating utensils or
drinking glasses, or other casual contact.

Risk factors of HCV transmission

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

DIAGNOSIS :
ACUTE:
1) Marked elevations in ALT (> 7 times) with or without
symptoms of acute hepatitis;
2) Negative tests for acute hepatitis A (IgM anti-HAV)
and acute hepatitis B (IgM anti-HBc); and
3) A positive anti-HCV screening immunoassay
(ICT,ELIZA, CIA) that is confirmed with either:
1. an immunoassay!
2. or a supplemental test, e.g., recombinant immunoblot
assay (RIBA ).
3. HCV RNA may be detected by PCR 1-3 weeks after
exposure, but viremia may be transient, i.e., a negative
qualitative HCV RNA does not preclude acute HCV
infection.

TESTING RECOMMENDATIONS FOLLOWING A

KNOWN EXPOSURE:
1) nucleic acid test for HCV RNA immediately after
exposure, at week 4 and at week 12;
2) anti-HCV by ICT or ELIZA immediately after
exposure and at week 12
3) serum ALT and AST immediately after exposure,
at week 4 and 12.
CHRONIC: A quantitative HCV nucleic acid test,
however, is required before initiating antiviral therapy,
If the quantitative HCV nucleic acid test is negative, the
more sensitive qualitative HCV nucleic acid test (PCR)
should be obtained.

Treatment and
Prevention
Treatment:
Antiviral therapy is beneficial in treating persons with

acute HCV infection.

Treatment interferon + ribavirin.
No vaccine available
Prevention:
Screening of blood, organ, tissue donors
High-risk behaviour modification
Blood and body fluid precautions

Hepatitis D

Hepatitis D is caused by

the Hepatitis D virus

( HDV)
Defective RNA
Occurs as co- or superinfection with HBV
Parenterally transmitted
Leads to severe course of
liver disease.
In 1987, normal
immunoglobulin
preparations were shown
to be anti-delta positive.

Mode of Transmission
Percutanous exposures
injecting drug use

Permucosal exposures
sex contact

HBV HDV Coinfection

Symptoms
ALT
Elevated

Titre

anti-HBs
IgM anti-HDV

HDV RNA
HBsAg

Time Exposure

Total anti-HDV

Prevention
Pre or post-exposure prophylaxis to prevent

HBV infection.
Education to reduce risk behaviours among
persons with chronic HBV infection.

Hepatitis E

HEV was confirmed in

1970s and early

1980s.
Initially referred to as
enterically
transmitted (or
epidemic) non-A, nonB hepatitis(NANB).

Distribution

HAV and HEV are associated with poor standards of

sanitation.
HEV has been recorded predominantly in Afghanistan,
China, India, Nepal, Pakistan and in parts of Central Asia,
Mexico and in parts of Africa.

INDIA
Common cause of Acute Fulminant Hepatitis in
adults.
Large outbreaks associated with sewage
contaminated drinking water include 1 in 1954
involving approximately 40,000 cases in Delhi, India.
In 1991, 79,000 cases were reported in Kanpur,
India.
Several outbreaks between 1989 and 1999 in AP,
MP, Delhi, Ahmedabad, Rajasthan have been
investigated by NICD. 80% of cases were 15 years
and above.
Males > Females

Transmission:
Faecal-oral route.(water-borne, food-born outbreaks)
Person to person transmission is uncommon.
Immunity:
Immunity has no role
Mortality:
Less than 1 %
HEV causes fulminant hepatitis and high fatality in
pregnant women.
Case fatality 20-40%
Animal Reservoir:
HEV zoonotic member
Detected in animal excreta(cows, pigs, goats and
rodents)

Incubation period:
2 weeks to 2 months (mean-40 days)
Clinical features:
Fever (disappears by the time of jaundice
appears)
Loss of appetite
Feeling of general ill health
Abdominal discomfort
jaundice
Laboratory findings:
ALT>2.5 times of upper limit
Serum Bilirubin> 2 mg%

Prevention and Control

Personal Hygiene and environmental sanitation
Ensure safe water supply
High level of residual chlorine, at least 0.5 ppm
Virus is killed by boiling of water

Anticipatory Action
Ensure water quality monitoring on regular basis in
addition to sanitary service and inspections by health
agencies and suppliers.
Disease surveillance through health facilities and
institutions.
People participation and education of community on all
aspects of prevention of Hepatitis by their own action.

Hepatitis F
Name was proposed following reports of

Hepatitis cases associated with waterborne transmission of virus distinguishable

from HAV and HEV.
Existence is not proven, but cases have
been reported in India, Italy, UK and USA.

Hepatitis G
AGENT:HGV is RNA virus and is similar to HCV but
only has 25 amino acids.
The virus is named after GB a 34 year-old surgeon who
contracted hepatitis and died from it.His serum was able
to infect monkeys and the "GB agent" was passaged in
monkeys over the years. In 1995-96 the virus was
identified as a distinct virus different from other
human hepatitis viruses (A, B, C, D, E) and was named
after the surgeon as HGV
Three genotypes of this virus were identified by
investigators at Abbott Labs, and termed GB-A, GB-B
and GB-C. GB-A and GB-B are likely tamarin viruses;
GB-C can infect humans.

CLINIAL FEATURES:
Hepatitis G virus infection is usually "clinically silent"
or mild hepatitis and nearly always chronic
Progression to cirrhosis with chronic hepatitis G
infection is probably very low.
Some studies report chronicity as high as HCV (up to
70 % )
Non-hepatic manifestations of this virus may well
exist
DIAGNOSIS: Only PCR is available in Agha Khan and
SKH and costs more than 2000 rupees per test
TREATMENT: Mainly supportive. In HBC+HGV and
HBV+HGV co-infection IFN + RBZL are effective.

TT Virus (Torque Teno Virus )

Belongs to Circoviridae family
Human virus with single stranded circular DNA genome
TTVs are prevalent in non-human primates and human

TTV can cross-infect

First reported in Japan (1997)

SEN virus
SEN virus (SEN-V) is a blood-borne, single-

stranded, non-enveloped DNA virus

Concurrent infections with hepatitis B virus,
hepatitis C virus, or human immunodeficiency
virus type 1 .
Cause post-transfusion hepatitis