Download Hepatitis viruses - University of Yeditepe Faculty of Medicine, 2011

HEPATITIS
HEPATITIS VIRUSES
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At least 6 viruses
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HAV
HBV
HCV
HDV
HEV
HGV?
HEPATITIS VIRUSES
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hepatitis alphabet of viruses includes at least six viruses, A
through E, and G
Although the target organ for each of these viruses is the
liver, and the basic hepatitis symptoms are similar, they
differ greatly in their structure, mode of replication, mode
of transmission, and in the time course and sequelae of the
disease they cause. :
Hepatitis A virus (HAV)
Hepatitis B virus (HBV)
Hepatitis C virus(HCV)
Hepatitis D virus (HDV
Hepatitis E virus (HEV)
HEPATITIS VIRUSES /HEPATITIS
 Liver
damage
 Icteric symptomes
Jaundice
Release of liver enzymes
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HEPATITIS VIRUSES
Hepatitis A, which is sometimes known as
infectious hepatitis,
(1) is caused by a picornavirus, a ribonucleic acid
(RNA) virus;
(2) is spread by the fecal-oral route;
(3) has an incubation period of approximately 1
month, after which icteric symptoms start
abruptly;
does not cause chronic liver disease;
rarely causes fatal disease.
SPREAD OF HAV WITHIN THE BODY
HEPATITIS A VIRUS/EPIDEMIOLOGY
Seropositivity rate of adults in various
countries:
 Sweden 13%
 USA
41-44%
 Yugoslavia 97%
 Taiwan
88%
 Turkey
65-above 95%
TIME
COUR
SE OF
HAV
INFEC
TION
HEPATITIS A VIRUS/LABORATORY
DIAGNOSIS
 Time
course of the clinical symptomes
 Identification of a known infected source
 Specific serologic tests

anti-HAV IgM by ELISA
HEPATITIS A VIRUS/TREATMENT,
PREVENTION & CONTROL
 Fecal-oral
spread
 Prophylaxis

Immune serum globulin

Before or early in the incubation period:
80-90% effective in preventing clinical
illness
 Vaccine:
appr)

killed HAV vaccine (FDA
For use in children or adults at risk
for infection
HEPATITIS B VIRUS
 Hepadnaviruses
Infect : liver, kidneys, pancreas
 Only humans and chimpanzees
HEPATITIS B VIRUS/STRUCTURE
Small
 Envelopped
 DNA genome
 Several unusual properties:
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Small (3200 bases) -circular-partly double-stranded DNA
 Encodes a reverse transcriptase
 Replicates through an RNA intermediate
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HEPATITIS B
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previously known as serum hepatitis,
(1) is caused by a hepadnavirus with a deoxyribonucleic acid
(DNA) genome;
(2) is spread parenterally by blood or needles, by sexual contact,
and perinatally;
(3) has a median incubation period of approximately 3 months,
after which icteric symptoms start insidiously;
(4) is followed by chronic hepatitis in 5% to 10% of patients; and
(5) is causally associated with primary hepatocellular carcinoma
(PHC).
More than one third of the world's population has been infected
with HBV, resulting in 1 to 2 million deaths per year.
The incidence of HBV is decreasing, however, especially in
infants, because of the development and use of the HBV subunit
vaccine.
UNIQUE FEATURES OF
HEPADNAVIRUSES
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Virus has enveloped virion containing partially doublestranded, circular DNA genome.
Replication is through a circular RNA intermediate.
Virus encodes and carries a reverse transcriptase.
Virus encodes several proteins (HBsAg [L, M, S]; HBe/HBc)
that share genetic sequences but with different in-frame
start codons.
HBV has a strict tissue tropism to the liver.
HBV-infected cells produce and release large amounts of
HBsAg particles lacking DNA.
The HBV genome can integrate into the host chromosome.
HEPATITIS B VIRUS/STRUCTURE
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Virion: Dane particule, 42nm in diameter
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Unusually stable for an envelopped virus
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Resist treatment with :
 ether,
 a low pH,
 Freezing,
 Moderate heating
transmission
HEPATITIS B VIRUS/STRUCTURE
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Virion: Dane particule, 42nm in diameter include:
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a polymerase
Reverse transcriptase activity
 Ribonuclease activity
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HBcAg
HBsAg, 3 forms:
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L>M>S glycoproteins, contains “a” determinant (goup- specific),
and “d” or “y” and “w” or “r”, type-specific determinants
HEPATITIS B VIRUS/REPLICATION
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“Unique!”
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Replicates through an RNA intermediate and produces and
releases antigenic decoy particules
HEPATITIS B VIRUS
The virus has
RNA-dependent DNA polymerase:
(Reverse transcriptase)
HEPATITIS B VIRUS
A
circular positive-strand RNA
intermediate is first synthesized by:
cell’s DNA dependent RNA
polymerase
RNA-dependent DNA polymerase:
a negative strand DNA is formed
positive RNA degragated
Positive strand DNA is initiated but stops
when the genome and the core enveloped
RESULT: partially double stranded DNA
HEPATITIS B
VIRUS/PATHOGENESIS&IMMUNITY
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HBV can cause:
Acute or
 Chronic,
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Symptomatic or,
 Asymptomatic
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disease...
HEPATITIS B
VIRUS/PATHOGENESIS&IMMUNITY
“It’s determined by the person’s immune response to the
infection”
HEPATITIS B
VIRUS/PATHOGENESIS&IMMUNITY
HBsAg and HBeAg in the blood
:
ongoing active infection
 The major source of infectious virus is blood
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Semen
Saliva
Milk
Vaginal & menstrual secretions
Amniotic fluid
HEPATITIS B
VIRUS/PATHOGENESIS&IMMUNITY
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Infants & young childrens are less able to resolve the
infection
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~90% infected perinatally become chronic carriers
HEPATITIS B VIRUS/EPIDEMIOLOGY
asymptomatic carriers foster the spread of the virus
 Routes of spread: sexual, parenteral, and perinatal
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HEPATITIS B VIRUS/EPIDEMIOLOGY
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Transmission:
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Contaminated blood, blood components
Needle sharing
Acupuncture
Ear piercing
Tattooing
Very close personel contact
The exchange of semen, saliva,
vaginal secretions (e.g., sex,
childbirth)
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HIGH-RISK GROUPS FOR HEPATITIS
B VIRUS INFECTION
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People from endemic regions (i.e., China, parts of Africa,
Alaska, Pacific Islands)
Babies of mothers with chronic hepatitis B virus
Intravenous drug abusers
People with multiple sex partners, homosexual and
heterosexual
Hemophiliacs and other patients requiring blood and blood
product treatments
Health care personnel who have contact with blood
Residents and staff members of institutions for the
mentally retarded
Hemodialysis patients and blood and organ recipients
HEPATITIS B VIRUS/CLINICAL SYNDRONNES
Chronic
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infection
5-10% of people with HBV infections
HEPATITIS B VIRUS/CLINICAL SYNDRONNES
Primary
hepatocellular carcinoma
80% of all cases of chronic HBV inf.
 One of the three most common cause of
cancer mortality in the world
 May become the first vaccinepreventable human cancer
 Latency period: 9 to 35 years
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HEPATITIS B VIRUS/LABORATORY
DIAGNOSIS
INTERPRETATION OF SEROLOGIC MARKERS OF HEPATITIS B
VIRUS INFECTION
Disease state
Serologic
reactivity
Anti-HBc
Anti-HBe
Anti-HBs
HBeAg
HBsAg
Infectious
virus
Early
+
+
Early
acute
+
+
+
Healthy state
Acute
+
+
+
Chronic
+
+
+
+
Late
acute
+/+/+
+
Resolved
vaccinat
ed
+
+/+
-
+
-
HBEAG
Secretory form of HBcAg
 Indicates viral replication and infectivity
 In some chronic infections
 HBV DNA is high
 No HBeAg
 Because of a mutation in core promoter or
precore region which encodes HBcAg
 +mutations in core region enhances severity ,
increase risk of cirrhosis
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ACUTE INFECTION
HBsAg
 AntiHBc-IgM
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Immunity:
 Anti-HBs ≥10IU/ml
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HBV INFECTION: NAT
1-HBV DNA PCR (real-time PCR:
quantitation:IU/ml)
-staging the disease
-prognosis detection
-monitoring therapy
2-HBV Genotyping:
Antiviral Resistance detection
HEPATITIS B VIRUS/PREVENTION&CONTROL
 Screening
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donated blood
HBsAg, anti-HBc
 Avoiding
intimate personal contact with
HBsAg (+)’s
 Avoiding the lifestyles that facilitate the
spread of the virus
 (High risk groups
 Vaccination
HEPATITIS B VIRUS/PREVENTION&CONTROL
 Universal
blood and body fluid precautions
(refer to HIV and retroviruses lesson)
PREVENTION, AND CONTROL
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Transmission of HBV in blood or blood products has been
greatly reduced by screening donated blood for the
presence of HBsAg and anti-HBc.
Additional efforts to prevent transmission of HBV consist
of avoiding sex with a carrier of HBV and avoiding the
lifestyles that facilitate spread of the virus.
Household contacts and sexual partners of HBV carriers
are at increased risk, as are patients undergoing
hemodialysis, recipients of pooled plasma products, health
care workers exposed to blood, and babies born of HBVcarrier mothers.
PREVENTION, AND CONTROL
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Vaccination is recommended for infants, children, and
especially people in high-risk groups
For newborns of HBsAg-positive mothers and people
accidentally exposed either percutaneously or permucosally
to blood or secretions from an HBsAg-positive person,
vaccination is useful even after exposure. Immunization of
mothers should decrease the incidence of transmission to
babies and older children, also reducing the number of
chronic HBV carriers. Prevention of chronic HBV will
reduce the incidence of PHC. is not readily inactivated by
detergents.
THE HBV VACCINES
subunit vaccines.
 The initial HBV vaccine was derived from the 22nm HBsAg particles in human plasma obtained
from chronically infected people.
 The current vaccine was genetically engineered
and is produced by the insertion of a plasmid
containing the S gene for HBsAg into a yeast,
Saccharomyces cerevisiae. The protein selfassembles into particles, which enhances its
immunogenicity.
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THE HBV VACCINES
The vaccine must be given in a series of three
injections, with the second and third given 1 and
6 months after the first.
 More than 95% of individuals receiving the full
three-dose course will develop protective
antibody.
 The single serotype and limited host range
(humans) help ensure the success of an
immunization program.
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UNIVERSAL BLOOD AND BODY FLUID
PRECAUTIONS
are used to limit exposure to HBV.
 It is assumed that all patients are infected.
 Gloves are required for handling blood and body
fluids; wearing protective clothing and eye
protection may also be necessary.
 Special care should be taken with needles and
sharp instruments.
 HBV-contaminated materials can be disinfected
with 10% bleach solutions
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HEPATITIS C AND G VIRUSES
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HCV
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was identified by molecular biologic means
in 1989
Predominant cause of NANBH virus
infections
Major cause of post-transfusion hepatitis
(before routine screening of the blood
supply for HCV)
HEPATITIS C VIRUS
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HCV
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> 170 000 000 (17x 107) carriers in the
world
Transmission similar to HBV but
“Greater potential for establishing
persistent, chronic hepatitis”
Cirrhosis
HCC
HEPATITIS C VIRUS/STRUCTURE &
REPLICATION
“HCV has never been isolated”
 “Only member of the Hepaciviridae” (family:
Flaviviridae)
 Enveloped
 Positive-sense RNA
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Encodes 10 proteins (2 glycoproteins, E1, E2)
6 groups of variants (clades), genotypes..
HEPATITIS C VIRUS/PATHOGENESIS
Cell-mediated immunopathology is responsible mainly
for producing the tissue damage
 Antibody to HCV is not protective!
 Immunity to HCV may not be lifelong
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HEPATITIS C VIRUS/EPIDEMIOLOGY
Is transmitted primarily in infected blood and sexually
 Almost all (>90%) HIV infected individuals who
are/were IVDUs are infected with HCV
 Almost 20 % of Egyptian blood donors are (+)
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HEPATITIS C VIRUS/CLINICAL
SYNDROMES
3 types of diseases
Acute hepatitis
(15% recovery)
chronic persistant inf.
(70%)
Cirrhosis
(15%)
HEPATITIS C VIRUS/CLINICAL
SYNDROMES
Acute HCV infection
similar to acute
HAV/HBV,
 Inflammatory response is less intense
 Symptoms
milder
 >80% asymptomatic
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HEPATITIS C VIRUS/LABORATORY
DIAGNOSIS
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Anti-HCV with ELISA
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Seroconversion within 7 to 31 weeks of
infection
HCV antigen with ELISA
HCV RNA with real-time PCR
 Genotyping
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HEPATITIS D VIRUS
~ 15 million people are infected with HDV in the world
 Cause of 40% of fulminant hepatitis infections
 Unique
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Uses HBV and target cell proteins to replicate and produce
its one protein
 “a viral parasite”
 HBsAg is essential for packaging the virus
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HEPATITIS D
VIRUS/STRUCTURE&REPLICATION
ssRNA genome
 ~ 1700 nucleotides
 Rod shaped (circular)
 Virion size ~ HBV
 Delta Ag surrounded by HBsAg containing envelope
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THE DELTA HEPATITIS VIRION
HEPATITIS D VIRUS/PATHOGENESIS
 Similar
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to HBV:
Spread in blood, semen, and vaginal secretions
It can replicate and cause disease only in people with
active HBV infections
A person can be coinfected with HBV & HDV, or
A HBV carrier can be superinfected with HDV
 Replication
of HDV results in cytotoxicity and
liver damage
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Unlike HBV, damage to the liver occurs as a result of
the directc cytopathic effect of the delta agent
combined with the underlying immunopathology of
the HBV disease
HEPATITIS D VIRUS/EPIDEMIOLOGY
 Worlwide
distribution
 Endemic in southern Italy, the Amazon
Basin, parts of Africa, and the Middle East
 Spread by the same routes as HBV
HEPATITIS D VIRUS/CLINICAL
SYNDROMES
 Increases
the severity of HBV infections
 > fulminant hepatitis than other H. viruses
HEPATITIS D VIRUS/LABORATORY
DIAGNOSIS
 Ag,
 Ab,
with
ELISA or RIA
 HDV RNA
DELTA VIRUS
The most unusual mode of replication
 Circular single stranded RNA
 Uses the host cell DNA dependent RNA
polymerase in the nucleus
 Needs the presence of HBV
 A defective virus
 HBsAg is necessary for packaging the virus
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HEPATITIS D VIRUS/TRE-PRE-CO
 No
known specific treatment
 Prevention of HBV
 HBV vaccine
HEPATITIS E VIRUS
 E-NANBH
Enteric/epidemic Non-A, Non-B hepatitis
 Predominently spread by the fecal-oral
route, esp. in contaminated water
 Worlwide
 Problematic in developping countries
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HEPATITIS E VIRUS
 Epidemics
in India, Pakistan, Nepal,
Burma, North Africa, Mexico
 Symptoms and course similar to those of
HAV
 Cause only acute disease
 Mortality rate associated with HEV
disease is x10 times that associated with
HAV disease (~1-2%)
HEPATITIS E VIRUS
 Mortality
rate associated with HEV
disease is x10 times that associated with
HAV disease (~1-2%)
 Serious in pregnant women:
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Mortality rate of approximately 20%
OTHER VIRUSES THAT CAN CAUSE HEPATIC
INFLAMMATION INCLUDE
Epstein-Barr virus (EBV);
 herpes simplex virus (HSV);
 mumps,
 rubella,
 rubeola,
 varicella-zoster virus;
 yellow fever virus;
 coxsackie B virus, and
 adenovirus.
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VIRUSES BEYOND A TO E
Approximately 15% to 17% of hepatitis infections
remain unexplained.
 Acute hepatitis and chronic hepatitis occur
sporadically, after transfusion and in organ
transplant recipients.
 Some such cases result in the development of
fulminant liver failure. The causative agents for
non-A to E hepatitis continue to be sought.
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VIRUSES BEYOND A TO E
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Candidate viruses include hepatitis F virus (HFV), HGV,
TTV, and SEN virus.
HFV was initially identified as a putative hepatitis virus
spread by the fecal-oral route; however, there is insufficient
evidence to corroborate this, and the identity of HFV is in
doubt.
Two viral agents related to hepatitis have been identified
and designated.
HGV is also known as hepatitis-GB virus (HGBV) (so
named after the initials of the patient from whom the virus
was isolated). There is considerable homology between
HGV and HGBV. Three different viruses were isolated and
designated GBV-A, GBV-B, and GBV-C. The role of HGV
and GBV-C in human disease, if any, remains
unestablished.
DIFFERENTIAL DIAGNOSIS OF ACUTE
HEPATITIS
Epstein-Barr virus
 Cytomegalovirus
 Herpes simplex virus
 Yellow fever
 Leptospirosis
 Q fever
 Human immunodeficiency virus
 Brucellosis
 Lyme disease
 Syphilis
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YELLOW FEVER
enzootic in central Africa, Central America, and
South America. More than 90% of cases occur in
Africa . Yellow fever is characterized by an
incubation period (3 to 7 days) much shorter than
that of hepatitis A, B, and C viruses. Patients can
present with a severe hepatitis.
 Yellow fever should be suspected in the recent
traveler to enzootic areas who did not receive
adequate immunization.
 The mortality rate in yellow fever approximates
20%.
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LEPTOSPIROSIS
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A zoonosis
Patients with infection present with an abrupt onset of
fever, chills, myalgias, and headache
They may have marked jaundice.
On physical examination, prominent conjunctival suffusion
is often noted.
Leukocytosis, which is uncommon in acute viral hepatitis,
may be prominent and together with urinary findings of
proteinuria, hematuria, and anuria should raise the
suspicion of leptospirosis.
The serum creatine phosphokinase is elevated in 50% of
patients. Marked jaundice accompanied by renal
dysfunction in a febrile patient with leukocytosis should
raise the possibility of Weil's syndrome, a severe form of
leptospirosis.
Q FEVER
is caused by the rickettsial agent Coxiella
burnetii
 Epidemiologic features linking exposure to farm
or wild animals and the finding of unique hepatic
granulomas (fibrin-ring granulomas are
suggestive but not pathognomonic) should lead
the clinician to suspect Q fever.
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