Download Altered & Disordered Physiology CH056

Biology of Disease CH0576
Hyperbilirubinaemia & Jaundice III
Viral Hepatitis
CH0576/RY
1
Viral Hepatitis
• A range of systemic viral infections can involve
the liver and lead to hepatitis e.g. EBV, CMV or
Yellow Fever.
• The term ‘viral hepatitis’ is restricted to
infection by a growing group of viruses which
have a particular affinity for the liver.
• Currently this group of unrelated viruses
includes Hepatitis A,B,C,D,and E .
CH0576/RY
2
Hepatitis A
• Hepatitis A is commonly called ‘infectious’
hepatitis.
• Hep A is a benign, self limiting disease with
an incubation period of around 2-6 weeks.
• HAV infection occurs around the world and
is endemic in areas of poor hygiene and
sanitation.
• Clinical disease tends to be mild or
asymptomatic, and is rare after childhood
CH0576/RY
3
Hepatitis A
• HAV is spread by the ingestion of virally
contaminated water and food, and is shed in
stools for about 2 to 3 weeks before and 1
week after the onset of an overt jaundice.
• Close personal contact with an infected
individual accounts for the spread of this
condition among certain groups:– Schools and nurseries
– Water sports enthusiasts (in contaminated water)
CH0576/RY
4
Hepatitis A
• In developed countries sporadic infections
are seen largely through the consumption
of contaminated shellfish, which are able
to concentrate the virus from sea water
contaminated by sewage outfalls.
• As HAV viraemia is only transient, blood
borne transmission of HAV only rarely
occurs and hence donated units are not
screened for the virus.
CH0576/RY
5
Hepatitis A Virus
• A small non-enveloped single stranded RNA
virus.
• Apparently not cytotoxic to hepatocytes
• At onset of symptoms, IgM antibodies
appear and serve as a marker of acute
infection.
• As the IgM titre rises, faecal shedding of
the virus ends.
• Lifelong immunity to re-infection by all
strains of HAV is gained.
CH0576/RY
6
Hepatitis B
• HBV is the cause of ‘serum hepatitis’ and
can produce a range of possible clinical
outcomes.
• Number of carriers of HBV, worldwide, is
estimated to be around 300,000,000.
• Unlike Hepatitis A, Hepatitis B viraemia
persists during a prolonged incubation
period of between 4 and 26 weeks.
CH0576/RY
7
Hepatitis B
• This virus can be spread by contact with
blood and body fluids/body secretions such
as:–
–
–
–
–
–
Semen
Saliva
Sweat
Tears
Breast milk
Pathologic effusions.
CH0576/RY
8
Hepatitis B
• There are a number of primary risk
categories for Hep B infection:–
–
–
–
–
–
Transfusion
Infusion of blood products
Dialysis
Needle stick injuries in health care workers
Intravenous drug abuse
Homosexual activity.
• In 1/3 of cases the source of transmission
is unknown.
CH0576/RY
9
Hepatitis B
• In endemic regions such as Africa and
Southeast Asia, the spread from a mother to
a neonate during birth is common (vertical
transmission)
• Neonates infected in this fashion often
become lifelong carriers of the infection.
• Hep B virus seems not to cause direct damage
to the liver cells.
• The damage to the liver is a consequence of
CD8+ T-cell activity against infected cells.
CH0576/RY
10
Hepatitis C
• Hepatitis C was previously known as ‘non-A non-B’
viral hepatitis, due to the failure to recognise the
infective agent.
• In 1989 Choo et al successfully identified the HCV
genome, using molecular cloning techniques.
• At this stage there were no culture techniques
which could successfully grow the virus, nor any
means of visualising the agent.
• Since then, major advances in our knowledge
regarding HCV have been made.
CH0576/RY
11
Hepatitis C
• HCV is an enveloped virus, and is a member
of the Flavivirus family.
• The envelope consists of host cell membrane
material, into which viral glycoproteins are
inserted.
• The genome is RNA, and consists of around
9,600 nucleotides.
• This encodes a single ‘polyprotein’ of around
3,000 amino acids length
CH0576/RY
12
Hepatitis C
• The ‘polyprotein’ is
cleaved into 10
structural and nonstructural proteins.
• Throughout the world 6
major HCV genotypes
have been described and
>100 subtypes.
• A major hindrance to
development of an
effective vaccine.
CH0576/RY
13
Hepatitis C
• To further complicate matters, within a
given infected individual there can be
identified several different, but related,
HCV sequences.
• These are referred to as ‘quasi-species’.
• These a re a reflection of the high
replication rate of the virus and indicates a
lack of effective proof-reading of the
RNA-dependent RNA polymerase.
CH0576/RY
14
Hepatitis C
• The virus predominantly replicates in the
cytoplasm of hepatocytes.
• HCV genome sequences have been isolated
from dendritic cells and also from B cells.
• One of the proposed receptors for the
virus is CD81, a component of the B-cell coreceptor.
• HCV transmission is primarily through
exposure to infected blood.
CH0576/RY
15
Hepatitis C
• It is thought that HCV is responsible for 9095% of transfusion associated hepatitis.
• In 1992 there was the development and
introduction of a screening test for blood
donations.
• This has greatly reduced the risk from
transmission by transfusion or transplantation.
• Infections still occur through intravenous drug
abuse, sex with infected partners and through
needle stick injuries in health care workers.
CH0576/RY
16
Hepatitis C
• Vertical transmission (mother to foetus) has
also been documented.
• Despite the screening of blood donations the
number of new infections in the U.S is
thought to be around 40,000 per annum.
• HCV has been estimated to have caused
persistent infection and chronic hepatitis in
>180,000,000 individuals globally.
CH0576/RY
17
Hepatitis C
• Incubation period ranges from 2-26 weeks.
• Persistent infection and chronic hepatitis
are classical hallmarks of HCV infection in
>50% of cases.
• Cirrhosis may be present at the time of
diagnosis or may develop over the following
5 to 10 years.
• There is an appreciable risk of the future
development of hepatocellular carcinoma.
CH0576/RY
18
Hepatitis C
• A significant number of individuals remain
asymptomatic and completely unaware of
infection until liver fibrosis, cirrhosis
and/or hepatocellular carcinoma develop.
• This may be decades after the acute subclinical infection with the virus.
• Treatments including the use of IFN and
ribavirin in combination have been
developed BUT <50% of the patients with
chronic HCV infection respond.
CH0576/RY
19
Clinical Course of HCV
• HCV RNA
 Serum ALT (alanine aminotransferase)
• HCV can leave little
serological evidence
following spontaneous
recovery.
• Abs can completely
disappear 10-20 years
after infection.
• The typical picture in
chronically evolving
acute hepatitis is seen
in fig.b.
CH0576/RY
20
Proposed Life Cycle of HCV
CH0576/RY
21
Hepatitis C & Lipids
• From the proposed life cycle of HCV it is
evident that lipid metabolism plays a role in
the disease pathogenesis.
• HCV is associated with LDL and VLDLs in
the plasma of infected individuals.
• The LDL receptor is a candidate for the
viral receptor/co-receptor on host cells.
• In chronic Hep C intracellular lipids
accumulate within infected hepatocytes ~
steatosis.
CH0576/RY
22
Hepatitis C & Lipids
• The HCV core protein seems to play a role
in steatosis:– Mice transgenic for the core protein develop
steatosis and hepatocellular carcinoma.
– Proposed mechanism being an increased lipid
peroxidation and development of mitochondrial
damage, leading to generation of reactive
oxygen species and damage to DNA within the
host cell.
CH0576/RY
23
Hepatitis C ~ Immune
Evasion
• HCV employs a varied range of evasion
strategies to produce persistent infection.
• These strategies are generally divided into
three categories:– Escape from T-Cell recognition,
– Resistance to immune attack,
– Counterattack i.e. active methods of fending
off the immune effector responses.
CH0576/RY
24
HCV ~ Escape
• HCV has a very high replication rate with
1010-1012 virions produced daily.
• This replication rate is thought to outrun
the immune response.
• Maximal viral titres are reached several
weeks before humoral/CMI responses are
detectable.
• CD8+ cells have been described as ‘stunned’
and are unable to secrete IFN- when viral
load is high.
CH0576/RY
25
HCV ~ Escape
• Ineffective proof reading by the HCV RNA
polymerase allows the generation of quasispecies – the virus keeps one step ahead of
the evolving immune response.
• Progressive quasi species generation is
associated with the generation of the
chronic form of hepatitis.
• Lack of quasi species generation tends to be
associated with a self-limited disease course.
CH0576/RY
26
HCV ~ Escape
• Any mutations which alter recognition sites
for T-cells or Abs will obviously help viral
escape and are associated with chronic
disease.
• HCV mutations can also affect peptide
binding by MHC antigens and prevent the
viral peptides being presented to T-cells.
• The non-cytopathic nature of HCV also aids
its escape:– Only very small levels of exogenous antigen
available for uptake by Dendritic cells.
CH0576/RY
27
HCV ~ Resistance
• During the replication of RNA viruses
there is the generation of double stranded
RNA (dsRNA).
• This usually leads to the activation of IFN
transcription factors and causes the
production of anti-viral type 1 IFN.
• Usually there is the inhibition of both
cellular and viral protein synthesis as a
result.
CH0576/RY
28
HCV ~ Resistance
• HCV appears to be highly resistant to the antiviral effects of ds-RNA.
• Mechanisms involved:– A) The NS3/4A serine protease blocks the effector
action of IRF3 (a transcription factor needed for the
production of IFN)
– B) HCV E2 acts as a decoy receptor for PKR (a protein
kinase which inhibits protein synthesis)
– C) A further HCV product, NS5A blocks PKR activation
by interacting with its catalytic site.
• Uninhibited cellular & viral protein synthesis
CH0576/RY
29
HCV ~ Counter-attack
• Studies indicate that HCV E2 protein causes
crosslinking of CD81 and inhibits the functions of
NK cells.
• There is inhibition of cytotoxicity, proliferation,
IFN- and TNF- secretion.
• Dendritic cells in chronic infected HCV individuals
are defective in their responses to foreign
antigens.
• Viral factors are proposed to be responsible for
this impaired DC function.
CH0576/RY
30
HCV ~ Counter-attack
• Acute HCV infection seems to cause
transient dysfunction of antigen specific
T-cells.
• Perforin content, lytic activity and ability
of CD8+ T-cells to proliferate are
significantly reduced.
• The CD8+ T-cells of chronically infected
individuals do not respond to HCV peptides
in in vitro function tests.
•  cytotoxicity, secretion of IFN-, and
proliferation in response to HCV antigens.
CH0576/RY
31
Hepatitis D
• This hepatitis virus is unusual in that it
shows a defective replication.
• HDV is absolutely dependent on HBV coinfection for its replication.
• Hepatitis D can hence occur with:– Exposure to serum containing HBV and HDV
– Superinfection of a chronic carrier of HBV
• The possible clinical outcomes in these
two scenarios are quite different.
CH0576/RY
32
Hepatitis E
• HEV mode of transmission is by the oral-faecal
route, with water borne transmission occurring
mainly in young to middle aged adults.
• A characteristic feature of HEV infection is
the high mortality rate among pregnant women
infected with the virus (around 20%)
• Average incubation period is 6 weeks.
• In most cases the disease is self-limiting and
not associated with chronic liver disease.
CH0576/RY
33
Clinical Syndromes
• A range of possible clinical syndromes may
develop after exposure to these hepatitis
viruses:
– Carrier state: without apparent disease
– Asymptomatic infection: serological evidence
only.
– Acute hepatitis: anicteric or icteric
– Chronic hepatitis: with or without progression
to cirrhosis
– Fulminant hepatitis: massive hepatic cell death.
CH0576/RY
34
Clinical Syndromes
• Not all of the hepatitis viruses can provoke all
of the possible clinical outcomes.
– HAV and HEV do not generate a carrier state nor
do they cause chronic hepatitis.
– Other infectious or non-infectious agents (e.g.
drugs and toxins) can lead to almost identical
syndromes.
– Hence serological studies are essential for the
differential diagnosis of viral hepatitis, and the
distinction between the different viral infections.
CH0576/RY
35