Hepatitis viruses

THE LIVER
FUNCTIONS OF THE LIVER:
– MAKES PROTEIN NEEDED FOR BLOOD
CLOTTING
– STORES VITAMINS, IRON AND GLYCOGEN
– METABOLIZES SUGAR, PROTEIN AND FAT
TO PRODUCE ENERGY
– REMOVES WASTE PRODUCTS AND
FILTERS TOXIC SUBSTANCES FROM
BLOOD
Enzymes (proteins) from the liver are normally
found in the blood as a result of normal aging
and degeneration of liver cells (called LFT’S –
liver function tests)
– ALT Almandine aminotransferase
– AST Aspartate aminotransferase
– GGTP Gamma -glutamyltransferase
 HEPATITIS - INFLAMMATION OF THE LIVER

CAUSED BY:

VIRUSES - HEPATITIS A, B, C, D, E, G
OTHER INFECTIONS
(MONONUCLEOSIS)
CHEMICALS
ALCOHOL
ACETAMINOPHEN

Acute hepatitis is where the disease develops quickly, has symptoms and lasts
less than 6 months.
Chronic hepatitis is where the symptoms and disease last longer than 6 months.

ACUTE HEPATITIS CAN RESOLVE TOTALLY OR GO ON TO A

CHRONIC STAGE
 Hepatitis Viruses. Diseases
Hepatitis A Hepatitis B Hepatitis C Hepatitis Delta Hepatitis E

Circular RNA
Similar to
Virus family Picornavirus Hepadnavirus Flavivirus similar to plant
Calicivirus
viroid

DNA (partially
Nucleic acid RNA (+ sense) RNA (+ sense) RNA (- sense) RNA (+ sense)
double strand)

Disease Infectious Non-A, non-B Enteric non-A,

Serum hepatitis
caused hepatitis hepatitis non-B hepatitis

Size ~ 28nm ~40nm 30 - 60nm ~ 40nm 30 - 35 nm

Envelope No Yes Yes Yes No

 A B C D E G
Non-A, non-B
Enteric
hepatitis
Infectious Serum non-A,
Disease Post Delta agent
hepatitis hepatitis non-B
transfusion
hepatitis
hepatitis
Blood and Blood and
Factors Blood and
body fluids body fluids Blood and
of the Feces body fluids Feces
Sexual Sexual body fluids
trasmiss. Sexual contact
contact contact
Parenteral Parenteral
Parenteral Parenteral
Enteric Percutaneou Percutaneou Enteric
Transmission Percutaneous Percutaneous
Fecal-Oral s s Fecal-Oral
Permucosal Permucosal
Permucosal Permucosal
Yes
Sexual (especially
transmission homosexu
al)
Chronic
No Yes Yes Yes No Yes
infection
Incubation 15 - 20
45 - 160 14 - 180 15 - 64 16 - 60 ?
 A B C D E G
Carcino- Hepatocellul Hepatocellular Hepatocellular
No No ?
genesis ar carcinoma carcinoma carcinoma

Cirrhosis No Yes Yes Yes No ?

Super-infection
with HBV -
often very
Usually Sometimes Usually (80%) Usually
severe with
Severity of mild. severe asymptomatic mild Asymptomatic
high mortality
disease Very low 1 -2% Up to 4% except in to mild
rate
mortality mortality mortality pregnancy
Co-infection
with HBV -
often severe
Behavior Safe
Behavior
Modification water
Prevention Vaccine Vaccine Modification
Blood No
HBV vaccine
screening vaccine

Chemo- Peginterferon/
therapy Ribovirin
 Hepatitis A virus
Picornaviruses family
RNA, naked, icosahedral, 15-20 nm,
cubic type of the symmetry

• can be cultivated in а
variety of tissue cell
cultures, but growth in cell
cultures requires long
adaptation
 HAV Symptoms

• Flu-like
– Fever, fatigue, nausea, vomiting, loss of
appetite, and general malaise
• Jaundice, pale colored stools, dark urine
• Children usually experience no symptoms
 HAV Prevention
• Hygiene (e.g., hand washing)
• Sanitation (e.g., clean water sources)
• Hepatitis A vaccine (pre-exposure)
– 2 shots within 6-12 months
– Twinrix
• Immune globulin (pre- and post-exposure)
Sterile preparation of concentrated antibodies (immunoglobulins) made
from pooled human plasma
– Only plasma tested negative for hepatitis B, HIV, and antibodies to
hepatitis C are used
• When administered within 2 weeks after an exposure to
hepatitis A virus, IG is 80 – 90% effective in preventing
hepatitis A
 Hepatitis B virus
Hepadnavirus family
DNA (in complete ds), enveloped,
40 nm , spiral type of the symmetry
 Three important HBV antigens are:
• (1) surface antigen (НВsАg),
- is produced during viral replication in amounts far in excess of that
needed for viral envelope production. It оссurs in the blood stream on
small spheres and filaments in quantities often 1,000 or more times
greater than complete virions.
- is responsible for the ability of the virus to infect its hosts;
! antibody to surface antigen (anti-НВsAg) confers immunity.
• (2) core antigen (НВcАg),
- represents the outer covering of the nucleocapsid.
! The presence of IgM antibody to НВcAg indicates acute rather than
chronic hepatitis В.
(3) е antigen (НВeAg),
а nonparticulate component of the viral core.
! The presence of НВeAg in the blood indicates а strong likelihood that
the blood is infectious.
 Structure of HBV
Hepatitis B surface
antigen HBsAg

lipid layer
from host cell
nucleocapsid

Hepatitis В core antigen HBcAg proteins (coded by

viral genes)
Hepatitis В e antigen HBeAg
Replication
 Three clinic forms are differentiated

• healthy HBV carriers,

• chronic persistent hepatitis (CPH) without viral

replication,

• chronic aggressive hepatitis (CAH) with viral

replication and a progressive course.
 Symptoms
– Jaundice
– fatigue/abdominal pain
– appetite loss
– nausea/vomiting
– mild fever
– dark urine
• One third of adults & 90% of children have no symptoms
• Symptoms last 1-4 weeks up to 6 months
• 90-95% recover within 6 months with lifelong immunity
• 50% develop acute liver disease
• Clinical course – 10% of adults who are infected do not clear the
virus* and develop what is called Chronic HBV infection.
– These patients develop chronic liver disease which can be either
persistently mild or aggressive.
20 – 25% of these patients die prematurely due to cirrhosis or liver
failure.

* 30 – 50% of all infected 1 to 5 year olds and 80 – 90% of all

infants develop chronic infection
Hepatitis B virus infection

Of the total number of

those infected, a small
percentage die from
cirrhosis (top picture)
and primary liver
cancer (bottom picture)
Blood test results at different times during acute
hepatitis В virus infection
IgM ANTI-HBc
 Hepatitis B: Disease Progression

Liver Cancer
(HCC)
5%-10% 1

2-6%

Acute Chronic Liver

Infection Infection Cirrhosis Transplantation
Death
10-30% 1
90% in perinatal
30-90% in children<5yrs old
5% in healthy adults Chronic HBV is the 6th
Liver Failure leading cause of liver
Higher in HIV, immune suppressed (Decompensation) transplantation in the
US4
23% within 5 years
1. Torresi J et al. Gastroenterology. 2000.
2. Fattovich G et al. Hepatology. 1995.
3. Moyer LA et al. Am J Prev Med. 1994.
4. Perrillo R et al. Hepatology. 2001.
 Laboratory Diagnostics in HBV Infections

Status Diagnostic test

Acute infection HBc-IgM, HBs-Ag
Vaccine immunity HBs-IgG
Recovered, healed HBs-IgG, HBc-IgG
Chronic, patient infectious HBe and HBs-Ag, PCR
Exclusion of HBV HBc-IgG negative
Serology inconclusive, mutants, Quantitative PCR
therapeutic monitoring
 The HBV Panel - Interpretation
Test Results Interpretation

HBsAg Negative The patient is susceptible to an HBV

anti-HBcAg Negative infection and has not been exposed
anti-HBsAg Negative previously to the virus
The patient has not been vaccinated
HBsAg Negative The patient is immune to HBV as a result
anti-HBcAg Positive of having been infected previously
anti-HBsAg Positive (indicated by the presence of anti-HBc
antibodies which would not occur if the
patient had been vaccinated)

HBsAg Negative The patient is immune because of

anti-HBcAg Negative vaccination against HBV
anti-HBsAg Positive
 HBsAg Positive The patient has an acute HBV infection. Any anti-
anti-HBcAg Positive HBsAg antibodies that have been made are
anti-HBcAg Positive complexed with the large amount of the antigen
IgM and are thus undetectable
anti-HBsAg Negative
HBsAg Positive The patient has a chronic HBV infection.
anti-HBcAg Positive The IgM anti-HBc has waned
anti-HBcAg Negative
IgM Negative
anti-HBsAg

The patient may be in the recovery phase of an

acute HBV infection. This patient could be infected
and thus a carrier of HBV. The inability to detect
HBsAg Negative HBsAg may result from it being complexed with
anti-HBcAg Positive anti-HBsAg antibodies in the "window" phase
anti-HBsAg Negative Other possible interpretations are that the patient is
distantly immune to HBV but the test was too
insensitive to detect anti-HBsAg.
There may also have been a false positive for anti-
HBcAg and the patient is actually uninfected.
 Treatment
• Supportive care is the major treatment. Anti-HBV immune globulin
is effective soon after exposure. It can also be given neonatally to
children of HBsAg-positive mothers. Ideally, the immune globulin
should be administered within 24 hours of birth or exposure and is
probably not effective after one week from exposure.
• There are three FDA-approved drugs for treating hepatitis B.
- Interferon-alpha 2b (Intron A - Schering-Plough) is a protein that
mimics the cell’s natural defenses against viral infection.
- Hepsera (Adefovir Dipivoxil – Gilead Sciences) is a nucleotide
analog that inhibits HBV DNA polymerase (reverse transcriptase).
Use is indicated for the treatment of chronic hepatitis B in adults
with evidence of active viral replication and either evidence of
persistent elevations in serum aminotransferases (ALT or AST) or
histologically active disease.
- Lamivudine (Epivir HBV - Glaxo SmithKlein). This is 3TC which is
a reverse transcriptase inhibitor that is also approved for use inn HIV
infections. As with all reverse transcriptase inhibitors, the appearance
of resistant mutants is a problem. Hepsera can be used in patients
with Epivir-resistant mutant virus.
 Vaccination
• This is the best preventative strategy. The current vaccines are subunit
vaccines made in yeast that has been transfected with a plasmid that
contains the S gene (that codes for HBsAg). The HBV vaccines go
under the names of Recombivax-HB (Merke) and Energix-B (Glaxo).
In addition, there is an approved vaccine against both HAV and HBV
(Twinrix – Glaxo). Another formulation for infants (Pediarix – Glaxo)
contains vaccines against diphtheria, tetanus, pertussis (whooping
cough), polio and HBV.

• There are normally three vaccinations for children (birth, 1 and 6

months) or adults to provide protective immunity. The vaccine is
recommended for children up to 18 years and for adults at high risk.
 Hepatitis D Virus
Now this virus belongs to
Togaviridae family,
genus Deltavirus

is defective RNA,
enveloped,
has same with HBV surface
Ag – HBsAg,

Modes of transmission:
•Percutanous exposures
– injecting drug use
•Permucosal exposures
– sex contact
Hepatitis D (HDV) or delta agent is a defective virus with
some similarities to plant viroids.
It cannot code for its own surface protein and thus in order to
produce more virus particles, it needs a helper virus;
this is HBV.
HDV is either acquired along with HBV (co-infection) or as
a super-infection of an already HBV-infected individual.
• Coinfection < 5%
- severe acute disease.
– low risk of chronic infection.
• Superinfection80%
– usually develop chronic HDV infection.
– high risk of severe chronic liver disease.
– may present as an acute hepatitis.
• Fulminant: 2 – 7.5%
 Hepatitis D - Prevention
• HBV-HDV Coinfection
– Pre or postexposure prophylaxis to prevent HBV
infection.
• HBV-HDV Superinfection
– Education to reduce risk behaviors among persons
with chronic HBV infection.
 Hepatitis Е virus (HEV)

• is а small (32-34 nm in diameter),

nonenveloped single-stranded
+ ve RNA virus of the Calicivirus
family
• 13 variants are divided into three
groups.
• very labile and sensitive
• Can only be cultured recently
• Clinical Features
– The period of infectivity following acute infection has not been
determined but virus excretion in stools has been demonstrated up
to 14 days after illness onset.
– In most hepatitis E outbreaks, the highest rates of clinically evident
disease have been in young to middle-age adults
– No evidence of chronic infection has been detected in long-term
follow-up of patients with hepatitis E.

• Incubation period: Average 40 days, range 15-60 days

• Case-fatality rate: Overall, 1%-3%
Pregnant women, 15%-25%
• Illness severity is increased with age
• Chronic sequelae: None identified
 Hepatitis E -
Epidemiologic Features

• 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.
 Prevention
– Prevention of hepatitis E relies primarily on the provision of
clean water supplies.
– Prudent hygienic practices that may prevent hepatitis E and other
enterically transmitted diseases among travelers to developing
countries include avoiding:
• drinking water (and beverages with ice) of unknown purity
• uncooked shellfish
• uncooked fruits or vegetables that are not peeled or prepared
by the traveler
– No products are available to prevent hepatitis E.
 Hepatitis C Virus - “non-A-non-B (NANB)
hepatitis.”

family Flaviviridae,
the genus Hepacivirus

6 genotypes of HCV are

known
 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
Hypothetical model of the HCV replication cycle. Upon infection of the host cell
(large rectangle) the plus-strand RNA genome (RNA) is liberated into the cytoplasm
and translated. The polyprotein is processed and viral proteins remain tightly
associated with membranes of the ER. Minus-strand RNA (–RNA) is synthesized by
the replicase composed of NS3–5B and serves as template for production of excess
amounts of plus strand. Via interaction with the structural proteins plus-strand RNA
is encapsidated. Particles are enveloped by budding into the lumen of the ER and
virus particles are exported via transit through the Golgi complex.
 Symptoms, or Lack of, in
Chronic HCV Infection

Symptomatic
37% 100
Cirrhosis 80
80

Patients (%)
7%
60

40

20

0
56% Fatigue
Asymptomatic
 HCV: Disease Progression
Time: 20-30 years

HCV infection

60-85%1

Chronic HCV Cirrhosis Hepatic Failure

20%-50%2 ~ 20%3
~20%4

Liver Transplant
Liver Cancer
Candidates
1. NIH Consensus Development Conference Statement; March 24-26, 1997.
2. Davis GL et al. Gastroenterol Clin North Am. 1994;23:603-613.
3. Koretz RL et al. Ann Intern Med. 1993;119:110-115.
4. Takahashi M et al. Am J Gastroenterol. 1993;88:240-243.
 Common Schedule and Type of HCV
Testing
Decision to Treat Process

Identification
Identification
and and
Planning
Planning Treatment

Diagnosis Prognosis
Stage Treatment Assess Response
Decision and Resistance
• HCV Ab • Liver biopsy • Genotyping • Quant HCV RNA
• HCV RNA • Comorbidities • Quant HCV
Assay
RNA
• IL28B genotype

Genotypes: 1-6 associated with response to therapy:

G1: 65-75% SVR
G2/3: 70-80% SVR
 Hepatitis G
• is a newly discovered form of liver inflammation caused by hepatitis
G virus (HGV), a distant relative of the hepatitis C virus.
– HGV, also called hepatitis GB virus, was first described early in
1996.
– HGV is a positive-strand RNA virus belonging to the family
Flaviviridae.
– Little is known about the frequency of HGV infection, the nature
of the illness, or how to prevent it. What is known is that
transfused blood containing HGV has caused some cases of
hepatitis.
 Clinical manifestation
– Some researchers believe that there may be a group of GB viruses,
rather than just one. Others remain doubtful that HGV actually
causes illness. If it does, the type of acute or chronic (long-lasting)
illness that results is not clear.
– Diagnosis is made by confirming the presence of HGV in the
blood by detecting HGV-RNA.
– When diagnosed, acute HGV infection has usually been mild and
brief.
– There is no evidence of serious complications, but it is possible
that, like other hepatitis viruses, HGV can cause severe liver
damage resulting in liver failure.
 Transmission

–Transfused blood containing HGV has caused some cases of hepatitis.

For this reason, patients with hemophilia and other bleeding conditions
who require large amounts of blood or blood products are at risk of
hepatitis G.
•HGV has been identified in between 1-2% of blood donors in the
United States.
•Also at risk are:
–Patients with kidney disease who undergo hemodialysis
–Injection drug users
–It is possible that an infected mother can pass on the virus to her
newborn infant
–Sexual transmission also is a possibility