2. THE LIVER
FUNCTIONS OF THE LIVER:
– MAKES PROTEIN NEEDED FOR BLOOD
– STORES VITAMINS, IRON AND GLYCOGEN
– METABOLIZES SUGAR, PROTEIN AND FAT
TO PRODUCE ENERGY
– REMOVES WASTE PRODUCTS AND
FILTERS TOXIC SUBSTANCES FROM
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
3. HEPATITIS - INFLAMMATION OF THE LIVER
VIRUSES - HEPATITIS A, B, C, D, E, G
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
4. Hepatitis Viruses. Diseases
Hepatitis A Hepatitis B Hepatitis C Hepatitis Delta Hepatitis E
Virus family Picornavirus Hepadnavirus Flavivirus
similar to plant
Nucleic acid RNA (+ sense)
RNA (+ sense) RNA (- sense) RNA (+ sense)
Size ~ 28nm ~40nm 30 - 60nm ~ 40nm 30 - 35 nm
Envelope No Yes Yes Yes No
5. A B C D E G
No Yes Yes Yes No Yes
Incubation 15 - 20
45 - 160 14 - 180 15 - 64 16 - 60 ?
6. A B C D E G
Cirrhosis No Yes Yes Yes No ?
Up to 4%
with HBV -
with HBV -
Prevention Vaccine Vaccine
7. Hepatitis A virus
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
8. HAV Symptoms
– Fever, fatigue, nausea, vomiting, loss of
appetite, and general malaise
• Jaundice, pale colored stools, dark urine
• Children usually experience no symptoms
10. HAV Prevention
• Hygiene (e.g., hand washing)
• Sanitation (e.g., clean water sources)
• Hepatitis A vaccine (pre-exposure)
– 2 shots within 6-12 months
• 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
12. 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.
13. Structure of HBV
Hepatitis B surface
from host cell
Hepatitis В core antigen HBcAg proteins (coded by
Hepatitis В e antigen HBeAg
17. Three clinic forms are differentiated
• healthy HBV carriers,
• chronic persistent hepatitis (CPH) without viral
• chronic aggressive hepatitis (CAH) with viral
replication and a progressive course.
– fatigue/abdominal pain
– appetite loss
– 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
19. • 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
* 30 – 50% of all infected 1 to 5 year olds and 80 – 90% of all
infants develop chronic infection
20. 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)
24. Hepatitis B: Disease Progression
Infection Cirrhosis Death
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.
23% within 5 years
Chronic HBV is the 6th
leading cause of liver
transplantation in the
90% in perinatal
30-90% in children<5yrs old
5% in healthy adults
Higher in HIV, immune suppressed
25. 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,
26. The HBV Panel - Interpretation
Test Results Interpretation
The patient is susceptible to an HBV
infection and has not been exposed
previously to the virus
The patient has not been vaccinated
The patient is immune to HBV as a result
of having been infected previously
(indicated by the presence of anti-HBc
antibodies which would not occur if the
patient had been vaccinated)
The patient is immune because of
vaccination against HBV
The patient has an acute HBV infection. Any anti-
HBsAg antibodies that have been made are
complexed with the large amount of the antigen
and are thus undetectable
The patient has a chronic HBV infection.
The IgM anti-HBc has waned
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 may result from it being complexed with
anti-HBsAg antibodies in the "window" phase
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.
• 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.
• 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.
31. Hepatitis D Virus
Now this virus belongs to
is defective RNA,
has same with HBV surface
Ag – HBsAg,
Modes of transmission:
– injecting drug use
– sex contact
32. 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.
– usually develop chronic HDV infection.
– high risk of severe chronic liver disease.
– may present as an acute hepatitis.
• Fulminant: 2 – 7.5%
36. Hepatitis D - Prevention
• HBV-HDV Coinfection
– Pre or postexposure prophylaxis to prevent HBV
• HBV-HDV Superinfection
– Education to reduce risk behaviors among persons
with chronic HBV infection.
37. Hepatitis Е virus (HEV)
• is а small (32-34 nm in diameter),
+ ve RNA virus of the Calicivirus
• 13 variants are divided into three
• very labile and sensitive
• Can only be cultured recently
38. • 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
40. Hepatitis E -
• 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 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.
43. Hepatitis C Virus - “non-A-non-B (NANB)
the genus Hepacivirus
6 genotypes of HCV are
44. 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
45. 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
46. 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.
51. 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.
Chronic HCV Cirrhosis Hepatic Failure
HCV: Disease Progression
Time: 20-30 years
52. Identification and Planning
Common Schedule and Type of HCV
Identification and Planning Treatment
• HCV Ab
• HCV RNA
• Liver biopsy
• Quant HCV
• IL28B genotype
• Quant HCV RNA
Decision to Treat Process
Genotypes: 1-6 associated with response to therapy:
G1: 65-75% SVR
G2/3: 70-80% SVR
54. 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
– HGV is a positive-strand RNA virus belonging to the family
– 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
55. 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
– 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.
–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
•HGV has been identified in between 1-2% of blood donors in the
•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
–Sexual transmission also is a possibility