VIRAL HEPATITIS

HEPATITIS VIRUS OUTLINE

 Definitions
 Classification

 Structure

 Multiplication

 Clinical manifestations

 Epidemiology

 Diagnosis

 Control
 HEPATITIS

 An inflammatory disease of the liver

‒ necrosis of hepatocytes

‒ mononuclear response destroys liver architecture

 Liver excretion of bile pigments such as bilirubin

into the intestine is interrupted

 BILIRUBIN

 Bilirubin: greenish-yellow pigment

accumulates in the blood and tissues

 Jaundice -

‒ yellow tinge in the skin and eyes

caused by bilirubin
 HEPATITIS SYMPTOMS

 Swelling and tenderness of liver

 Jaundice -yellow tinge in the skin
and eyes
 Dark urine
 Transaminase, alkaline phosphatase
levels increased
 HEPATITIS TYPES

 Hepatitis A - HAV "infectious hepatitis"

 Hepatitis B - HBV "serum hepatitis"

 Hepatitis C - HCV Blood to Blood

 Hepatitis D - HDV Delta virus

 Hepatitis E - HEV similar to type “A”

HEPATITIS A VIRUS

“Infectious hepatitis”

“Epidemic hepatitis”

HAV
 HEPATITIS A
CLINICAL MANIFESTATIONS

 Asymptotic or anicteric in children

 3-5 week incubation period
 liver inflammation
 Malaise - flu like symptoms
 Self limiting
 Low mortality
 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
 HEPATITIS A VIRUS
STRUCTURE

 Picornavirus

 Only one serotype

 Enterovirus type 72
 27-29 nm icosahedral
 Naked ssRNA Virus
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)
 HEPATITIS A
DIAGNOSIS
 Acute infection is diagnosed by the detection of
HAV-IgM in serum by EIA.
 Past Infection i.e. immunity is determined by the
detection of HAV-IgG by EIA.
 Cell culture – difficult and take up to 4 weeks, not
routinely performed
 Direct Detection – EM, RT-PCR of faeces. Can
detect illness earlier than serology but rarely
performed.
 HEPATITIS A
CONTROL

 No specific control
 Improve hygiene and sanitation
 Human immunoglobulin
 HAV vaccines in clinical field trials
 Hepatitis A Control
Vaccine
 Hepatitis A vaccine is an inactivated (killed) vaccine.
 2 Doses are needed that are given at least 6 months
apart.
 It can be considered for
 those traveling to countries where hepatitis A is common,
 Drug Abusers
 Heterosexuals
 have a chronic liver disease such as hepatitis B or hepatitis C
 are being treated with clotting-factor concentrates
 HEPATITIS B

“Serum hepatitis”
HBV
 Double stranded DNA virus,the + strand not
complete
 Replication involves a reverse transcriptase.
 HEPATITIS B
STRUCTURE

 Double stranded DNA virus, the + strand not complete.

 circular, 3200 nucleotides
 Enveloped icosahedral virus,42 nm

 Replication involves a reverse transcriptase.

3 FORMS OF HBV
 Hepatitis B Virus
Modes of Transmission
 Sexual - sex workers and homosexuals are
particular at risk.
 Parenteral – Intravenous drug abusers(IVDA),
Health Workers are at increased risk.
 Perinatal - Mothers who are HBeAg positive are
much more likely to transmit to their offspring
than those who are not. Perinatal transmission is
the main means of transmission in high prevalence
populations
Concentration of Hepatitis B Virus
in Various Body Fluids

 High - Blood,Serum,Wound exudates

- Semen,Vaginal fluid,Saliva
 Moderate
- Urine,Feaces,Sweat,Tears,
 Low/not detectable
- Breastmilk
 Hepatitis B - Clinical Features
 Incubation period: Average 60-90 days
Range 45-180 days
 Clinical illness (jaundice): <5 yrs, <10%
5 yrs, 30%-50%
 Acute case-fatality rate: 0.5%-1%
 Chronic infection: <5 yrs, 30%-90%
5 yrs, 2%-10%
 Premature mortality from
chronic liver disease: 15%-25%
 Spectrum of Chronic Hepatitis B
Diseases/Manifestations
1.Chronic/Persistent Hepatitis - asymptomatic
2. Chronic Active Hepatitis - symptomatic
exacerbations of hepatitis
3. Cirrhosis of Liver
4. Hepatocellular Carcinoma
 HEPATITIS B
HOST DEFENSES

 Cell mediated Immunity

 important
for recover in acute phase
 autoimmune liver damage in chronic infections

 Humoral Immunity
 not
always protective
 HBsAg for Vaccines

 Interferon
 notdetected during infection
 exogenous application effective
 HEPATITIS B INFECTIONS
 Targets the liver
 Cause focal necrosis, leading to larger areas of necroses
 Jaundice
- If recovery occurs, liver function often returns to normal
- Substantial damage cannot be reversed
 HBV and HCV have been associated with hepatocellular
carcinomas
 HBV can cause rash, arthritis, vasculitis and glomerulonephritis
 Fatality Rates
 Hep A: <0.5% (increases after age 40)
 Hep B: 1-2% (chronic in 5-10% of infections)

 Hep C: 0.5-1% (chronic in 70-90% of infections)

 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
 Treatment
 Interferon - for HBeAg +ve carriers with chronic active hepatitis. Response rate
is 30 to 40%.
 alpha-interferon 2b (original)
 alpha-interferon 2a (newer, claims to be more efficacious and efficient)
 Lamivudine - a nucleoside analogue reverse transcriptase inhibitor. Well
tolerated, most patients will respond favorably. However, tendency to relapse on
cessation of treatment. Another problem is the rapid emergence of drug
resistance.
 Adefovir – less likely to develop resistance than Lamivudine and may be used
to treat Lamivudine resistance HBV. However more expensive and toxic
 Entecavir – most powerful antiviral known, similar to Adefovir
 Successful response to treatment will result in the disappearance of HBsAg,
HBV-DNA, and seroconversion to HBeAg.
 Telbivudine (Tyzeka, Sebivo) Approved in October 2006 by the FDA for adults.
Several clinical trials have reported it to be more effective than lamivudine and
adefovir.
 Prevention
 Vaccination - highly effective recombinant vaccines are now
available. Vaccine can be given to those who are at increased
risk of HBV infection such as health care workers. It is also
given routinely to neonates as universal vaccination in many
countries.
 Hepatitis B Immunoglobulin - HBIG may be used to protect
persons who are exposed to hepatitis B. It is particular
efficacious within 48 hours of the incident. It may also be given
to neonates who are at increased risk of contracting hepatitis B
i.e. whose mothers are HBsAg and HBeAg positive.
 Other measures - screening of blood donors, blood and body
fluid precautions.
HEPATITIS C

HCV
Blood to Blood
Non -A Non-B
 HEPATITIS C
CLINICAL MANIFESTATIONS

 Resembles HBV
 persistent carrier state

 50% of patients have chronic liver damage

 associated with hepatocellular carcinoma

 Hepatitis C - Clinical Features
Incubation period: Average 6-7 wks
Range 2-26 wks
Clinical illness (jaundice): 30-40% (20-30%)
Chronic hepatitis: 70%
Persistent infection: 85-100%
Immunity: No protective
antibody
response
identified
Chronic Hepatitis C Infection
 The spectrum of chronic hepatitis C infection is
essentially the same as chronic hepatitis B
infection.
 All the manifestations of chronic hepatitis B
infection may be seen, albeit with a lower
frequency i.e. chronic persistent hepatitis, chronic
active hepatitis, cirrhosis, and hepatocellular
carcinoma.
 Risk Factors Associated with
Transmission of HCV
 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
 Laboratory Diagnosis
 HCV antibody - generally used to diagnose hepatitis C
infection. Not useful in the acute phase as it takes at least
4 weeks after infection before antibody appears.
 HCV-RNA - various techniques are available e.g. PCR
and branched DNA. May be used to diagnose HCV
infection in the acute phase. However, its main use is in
monitoring the response to antiviral therapy.
 HCV-antigen - an EIA for HCV antigen is available. It is
used in the same capacity as HCV-RNA tests but is much
easier to carry out.
 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.
 Protease inhibitors - The first protease inhibitors licensed
were boceprevir (Victrelis) and telaprevir. They have been
superseded by newer drugs such as Simeprevir (Olysio)
and sofosbuvir (Sovaldi).
 In 2014, the FDA approved the combination of
ombitasvir/paritaprevir/ritonavir and dasabuvir (Viekira
Pak ) for the treatment of genotype 1 chronic hepatitis C
infection in adults.
HEPATITIS D
HDV
 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
HEPATITIS D

 Dependovirus, it is defective and cannot

produce infection unless the cell is also infected
with HBV.
 Viroid - a naked strand of RNA that enters the
cell in piggy-back fashion.
 HEPATITIS D
CLINICAL MANIFESTATIONS

 Dual infection is more severe than HBV

 fulminating hepatitis
 severe rapidly progressive hepatitis
 severe exacerbations
 HEPATITIS D
STRUCTURE

 35-37 nm virus particle

 shares coat protein of HBV
 small RNA genome
 one serotype
 HEPATITIS D
EPIDEMIOLOGY
 Percutanous exposures
- injecting drug use
 Permucosal exposure
- sex contact
 Hemophiliacs and IV drug
 usersContaminated blood and blood
products
GEOGRAPHIC DISTRIBUTION OF HDV
 HEPATITIS D
DIAGNOSIS

 Clinical manifestations
 Delta antigen
 Immunofluorescence

 RIA

 ELISA

 Anti delta antigen

 same as above
HEPATITIS E VIRUS
 HEPATITIS E
 fecal/oral route
 predominantly found in developing countries but
is world wide.
 symptoms similar to HAV but mortality 1-2%
(ten times that of Hepatitis A).
 epidemics - India, Pakistan, Nepal, Burma,
North Africa and Mexico.
 HEPATITIS E VIRUS
 now classified as a member of the genus Orthohepevirus in the
Hepeviridae family
 unenveloped RNA virus, 32-34nm in diameter
 +ve stranded RNA genome, 7.6 kb in size.
 4 genotypes: genotype 1 (Asia), genotype 2 (Africa and
Mexico), genotype 3 (Europe and North America) and
genotype 4 (Asia)
 very labile and sensitive
 Can only be cultured recently
 Hepatitis E -
Epidemiologic Features
 Most outbreaks associated with faecally contaminated drinking
water.
 Overcrowded Primitive populations.
 Several other large epidemics have occurred since in the Indian
subcontinent and the USSR, China, Africa and Mexico.
 Minimal person-to-person transmission.
Prevention and Control Measures for
Travelers to HEV-Endemic Regions
 Avoid drinking water (and beverages with ice) of unknown
purity, uncooked shellfish, and uncooked fruit/vegetables
not peeled or prepared by traveler.

 A recombinant vaccine called HEV 239 has been

developed and is licensed for use in China.