Download Hepatitis Viruses

Hepatitis Viruses
HAV, HBV
NonA-NonB: HCV, HDV, HEV
Hepatitis
Hepatitis (plural hepatitides) is an inflammation of
the liver characterized by the presence of
inflammatory cells in the tissue of the organ. The
name is from the Greek hepar meaning liver, and
suffix -itis, meaning "inflammation.
Clinical manifestations of hepatitis are virtually the
same.
Hepatitis
The condition can be self-limiting (healing on its
own) or can progress to fibrosis (scarring) and
cirrhosis.
Acute: < 6 months
Chronic: > 6 months
Causes: Hepatitis or some other viruses. Alcohol,
certain medications and plants.
HAV
Disease
Hepatitis A (Infectious hepatitis)
Important properties
Typical enterovirus (enterovirus72) classified in
Picornavirus. Recently in new genus: Hepatovirus.
Single stranded RNA genome, positive sense,
Non - enveloped icosahedral nucleocapsid, 27-32 nm
HAV replicates in the cytoplasm of the cell
One serotype
Humans and chimpanzees are the only natural hosts
Replicative cycle
A positive strand RNA:
Genome replication occurs by synthesis of a
complementary negative strand which then serves
as the template for the positive strands which are
needed both for replication and protein synthesis.
Against other Picornavirus, it requires an intact
eukaryote initiating factor 4G (eIF4G) of the cell
for the initiation of translation.
Transmission & Epidemiology
Transmitted by fecal-oral (water, food, flies) and
parenteral route.
Virus in feces 2 weeks before the symptoms. So
quarantine of patients is ineffective.
In developing countries and regions with poor
hygiene standard, children are the most frequently
infected group.
40% of all acute viral hepatitis is caused by HAV.
Transmission & Epidemiology
As incomes rise and access to clean water increases,
the incidence of HAV decreases.
Mostly seen in susceptible young adults often during
trips to countries with a high incidence or contact
with infectious persons.
Pathogenesis
HAV replicates in gasterointestinal tract epithelial cells and
spreads to the liver via the blood.
Very low level of viremia
Hepatocytes are infected. HAV infection of cultured cells
produces no cytopathic effect.
Immune attack on the hepatocytes plays no role in
pathogenesis (A difference with HBV).
The level of viremia is low and chronic infection does not
occur.
The infection cannot be distinguished pathologically from
other hepatitis infections.
Acute hepatitis A infection can vary from being an
asymptomatic condition to being severe enough to cause
fulminant (sudden and severe) liver failure.
Clinical findings (HAV)
Incubation period: 2-6 weeks, average 1 month
Usually resolve spontaneously in 2-4 weeks.
No chronic infection or chronic liver disease
10-15% of patients might
experience a relapse of symptoms
during the 6 months after acute illness.
Case fatality rate: 0.5%
mainly in elder people.
Clinical findings (HAV)
No clinical signs and symptoms in over 90% of infected
children.
Fever
Anorexia (loss of appetite)
Nausea
Vomiting
Jaundice (icterus)
Fatigue
Abdominal pain
Itching
weight loss
Hepatomegaly
Bile removed from blood and excreted in urine, giving it a
dark amber colour.
Feces light in colour due to lack of bilirubin in bile.
Fever
Anorexia
Nausea
Vomiting
Jaundice
fatigue
Abdominal pain
weight loss
itching skin
Hepatomegaly
Bile in urine and
stool
Clinical findings (HAV)
> 80% of adults show symptoms and majority of
children having asymptomatic infections.
Alaninamino transferase (ALT) = Alaninamino
transferase level is much higher than normal: a nonspecific sign of HAV infection.
ALT comes from the liver cells damaged by the virus.
Immunity
Immune response is initially IgM antibody detectable
at the time jaundice appears.
The appearance of IgM is followed 1-3 weeks later
by the production of IgG antibody which provides
lifelong protection.
Laboratory diagnosis
Samples: Blood, Stool
Cell culture in Resus monkey cells but no CPE
Measuring IgM and IgG titer, especially IgM
antibody in the blood.
The liver enzyme alanine transferase (ALT).
PCR
Interpretation of Diagnostic Tests for HAV
Infection
HAV IgG
HAV IgM
Interpretation
Positive
Positive
Acute HAV infection
Negative
above)
Positive
Acute HAV infection (earlier phase than
Positive
protective
immunity
Negative
No acute HAV infection - person has
Negative
Negative
No acute HAV infection and no immunity
at risk for getting HAV in future
Treatment
A self-limited disease (Resolves itself spontaneously)
No antiviral therapy
Rest, avoid fatty food and alcohol
Prevention
Vaccination (by injection):
protection starts 2-4 weeks after vaccination. The
second booster is given six to twelve months later.
Passive immune prophylaxy
Sanitation by using Killing methods:
Boiling for 1 min
Sodium hypochlorite for 5 min
Chlorin treatment (drinking water)
HBV
A member of hepadenavirus
42-nm enveloped virion with an icosahedral
nucleocapsid
Partially double-strand circular DNA genome
HBV
42-nm virions, 22-nm
spheres, long filaments
22 nm wide
Antigenes and fragments
HBsAg (important both in diagnosis and immunization)
DNA-dependent DNA polymerase
3 different types of particles:
HBs Ag (42-nm virions, 22-nm spheres, long filaments
22 nm wide)
HBcAg (Core antigen )
HBe Ag (an indicator of transmissibility)
Serotypes based on HBsAg
HBsAg:
A group-specific antigen, ‘a’ and 2 sets of exclusive
epitopes, d or y and w or r leading to 4 serotypes:
adw, adr, ayw, ayr which are useful in epidemiologic
studies.
W  adw
d
a
r  adr
w  ayw
y
r  ayr
HBV Genotypes
Eight genotypes (A-H) according to overal
nucleotide sequence variation of the genome differing
by at least 8% of their sequence.
They have a distinctive geographical distribution
used in tracing the evolution and transmission of the
virus.
Differences between genotypes affect the disease
severity, course and likelihood of complications.
Humans are the only natural host of HBV
Replicative cycle
• DNA polymerase synthesize the missing portion of
DNA
Fully double-strand circular DNA in
nucleus
Some DNA copies integrates into
hepatocyte DNA /// Some DNA copies serves as a
template for mRNA synthesis
mRNA
functions both in protein synthesis and template for
the DNA minus strand (by RNA-dependent DNA
polymerase)
DNA minus strand serves as
template for plus strand.
Clinical finding
Incubation period: 2-3 months
The acute disease is similar to that of HAV.
Symptoms in HBV tend to be more severe than
HAV.
Most chronic carriers are asymptomatic.
Pathogenesis
Entering HBV the blood
infecting hepatocytes
necrosis and inflammation (Immune attack
against viral antigens on infected hepatocytes).
Chronic carriers (carriers of HBsAg ) are
asymptomatic.
Chronic hepatitis. Hepatitis with no apparent liver
clinical involvement.
Fulminant hepatitis. Occurrence: 1-2%, Highly and
fulminant necrosis of lever paranchim. 60-90% is
lethal. (Increase of Alaninamino transferase (ALT or
SGPT) and Aspartat transferase (AST or SGOT).)
Chronic persistent hepatitis. (probably due a persistent
infection of hepatocytes mediated DNA integrated
into cell DNA). Largeness of liver, increase of liver
enzyms.
Chronic active hepatitis may leading to chronic
necrosis of liver cells and paranchim (cirrhosis),
hepatocellular carcinoma and death.
Transmission & Epidemiology
Blood is Most important way of transmission.
In addicts using intravenous drugs.
Sexual transmission.
Mother to child during birth or breast feeding.
Immunization reduces the incidence.
Laboratory diagnosis
Samples
Blood is the best.
Liver biopsy
Cell culture and CPE:
Not affective
ELISA and Immunoassay
Laboratory diagnosis
Immunoassay for HBs Ag
HBsAg during the incubation period and mostly
during the prodome and acute disease.
Prolonged presence of HBsAg indicates carrier state
and the risk of chronic hepatitis.
Laboratory diagnosis
Windows phase: no HBsAg and HBsAb but HBcAb
HbeAg: During incubation period and is present during
prodrome and early acute disease (an indicator of
transmissibility).
HBeAb indicates low transmissibility.
DNA polymerase during incubation and early in the
disease but assay not available in clinical lab.
Treatment & Prevention
Alpha interferon
Lamivudine (inhibits hepatitis B viral DNA
synthesis)
Baraclude (inhibiting hepatitis B viral DNA
synthesis)
Rest, combined with a high protein/high
carbohydrate diet to repair damaged liver cells.
Prevention by using vaccine and hyperimmune
globulin
No one with a history of hepatitis (of any type)
should donate blood.
NON-A, NON-B hepatitis viruses
HCV
Distributed worldwide
The most major agent of Non-A, Non-B
An enveloped single-strand RNA virus (a
flavivirus).
Incubation period: an average of 2 months
No immunity
HCV
HCV
It has infected 200 million people worldwide.
The leading cause of cirrhosis, a common cause of
hepatocellular carcinoma
The leading reason for liver transplantation.
Coinfection with HIV is common.
Prevalence is higher in some countries in Africa and
Asia. Egypt has the highest serovalence for HCV
(20% in some areas).
Transmission
The way of transmission is the same as HBV:
Unsterilized injection equipment
Transfusion of unscreened blood
Sexual contacts
Pathogenesis
It is often asymptomatic but progress to scarring of
the liver (fibrosis) and advanced scarring
(cirrhosis) and complicated into liver cancer after
many years.
Persistent infection are common and most patients
develop chronic HCV lasting more than 6 months.
Clinical finding
Generalized signs and symptoms is the same as HBV.
Symptoms suggestive of liver disease are typically
absent until substantial scaring of the liver has
occurred.
HCV
Up to 80% of cases go to chronic forms tend to cause
cirrhosis (20-50%) or hepatocellular carcinoma (525%).
Mild infection (only 25%) show jaundice. Most cases
are asymptomatic
HCV genotypes
There are at least 6 genotypes (HCV-1 to HCV-6)
The more common in the middle east and Africa is
genotype 4.
HCV genotypes are related with human races.
Diagnosis
It is based on serologic methods (ELISA) for
detecting HCV antibodies.
It can detect 80% of patients within 15 weeks after
exposure and > 97% by 6 months.
As immunocompromised individuals never develop
antibodies to the virus, RNA testing (PCR) should
be considered when antibody testing is negative.
Diagnosis
Elevated liver enzymes, alanin amino transferase
(ALT) = (sGPT) and leucine amino transferase
(LAT)= (sGOT)
Treatment
Interferon
Ribavirin
50% of chronic cases do not respond to therapy.
There is a small chance of clearing the virus
spontaneously in chronic HCV carriers (0.5% 0.74%).
HEV
An enterically transmited virus
Nonenveloped, single-stranded RNA virus (from
calcivirus).
Diagnosis is serologic (ELISA) based on IgM and
IgG
No antiviral agent for treatment
HDV
(Delta agent)
Single-stranded circle RNA
RNA genome surrounded by an envelope composed
of HBsAg.
A defective virus as its genome does not code for its
own envelope protein.
HDV can only replicate in HBV-infected cells.
Delta antigen is a distinctive determinant present in
this virus but not in HBV.
HDV
HDV + HBV infection tends to be a fulminant
hepatitis.
Transmission the same as HBV
A chronic carrier state can occur.
Infection can be detected by the appearance of IgM
to delta antigen.
No treatment
No vaccine
HGV
A Flavivirus
Single stranded RNA, enveloped
Transmission by blood products
Not detected as epidemic in Iran
Lab detection is normally by PCR. Not
cultivable on cell culture
No treatment or vaccination