HEPATITIS

Dr Seye Adeniran
 WHAT IS HEPATITIS?
Hepatitis is an inflammation of the liver
tissue.
It is characterised by the destruction of
a number of liver cells and the presence
of inflammatory cells in the liver tissue.
The condition can be self-limiting or can
progress to fibrosis, cirrhosis or liver
cancer.
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Hepatitis can manifest as one
of the following, namely;
1.Acute.
2.Chronic.
3.Fulminant.

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• ACUTE HEPATITIS: Lasts < 6 months.
• CHRONIC HEPATITIS: Lasts > 6 months.
• FULMINANT HEPATITIS: severe
impairment of the liver’s synthetic function
due to massive hepatic cell necrosis from
acute injury.
injury Patients rapidly develop severe
and life-threatening liver failure. This can
happen within hours, days or sometimes
weeks (usually < 8 weeks; 2 months).
months It is a
rare complication of acute hepatitis.
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 CAUSES OF HEPATITIS
1. INFECTION:
– Viruses: HAV, HBV, HCV, HDV, HEV, HGV.
– Parasites: Trypanosoma cruzi, Leishmania species,
Plasmodium species, Entamoeba histolytica,
Echinococcus granulosus, Fasciola hepatica, Clonorchis
sinensis.
– Bacteria: Samonella, Mycobacteria species, Tropheryma
whipplei, Treponema pallidum, Coxiella burnetii,
and Rickettsia species.
2. METABOLIC: Alcohol (most common in western
world), drugs (PCM), toxins (CCL4, amanita phalloides).

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3. GENETIC: a1AT, Wilson disease,
haemochromatosis.
4. AUTOIMMUNE: is a chronic hepatitis
seen in persons with heterogeneous set
of immunologic diseases. Usually run
an indolent or severe course and
responds to immunosuppressive
therapy.
5. OTHERS: glycogen storage disease,
ischaemia, biliary atresia, cholestasis.
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 VIRAL HEPATITIS
The term viral hepatitis refers to a
group of inflammatory diseases of
the liver caused by viruses that
have special affinity for human
liver cells.
Such viruses are referred to as
THE HEPATOTROPIC VIRUSES. VIRUSES
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• Some other viruses, such as the
yellow fever virus, Ebola virus and
the Lassa fever virus, also cause
inflammation of the liver but they do
this as part of a multi-organ
involvement.
• For this reason, such viruses are not
considered usually together with
hepatotropic viruses.
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 HEPATITIS VIRUSES

• Hepatitis A (HAV) Picornaviridae (1973).

• Hepatitis B (HBV) Hepadnaviridae (1970).
• Hepatitis C (HCV) Flaviviridae (1988).
• Hepatitis D (HDV) ? (1977).
• Hepatitis E (HEV) (Caliciviridae) (1983),
Hepeviridae.
• Hepatitis F – Not separate entity – Mutant
of B Virus.
• Hepatitis G (HGV) Flaviviridae (1995).

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 TYPE OF HEPATITIS
A B C D E
Blood Blood Blood
SOURCE OF Feces Feces
Blood derived Blood derived Blood derived
VIRUS
Body fluids Body fluids Body fluids

ROUTE OF Percutaneous Percutaneous Percutaneous

Feco-oral Feco-oral
TRANSMISSION Permucosal Permucosal Permucosal

CHRONIC
No Yes Yes Yes No
INFECTION

Pre or Post
Ensure
Pre or Post Exposure Pre or Post
Safe
PREVENTION Exposure Immunization Blood donor Exposure
Drinking
Immunization Blood donor Screening Immunization
Water
screening

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 HEPATITIS A VIRUS

NAKED RNA VIRUS

RNA

Related to enteroviruses, formerly known

as Enterovirus 72, now put in its own
family: HEPTOVIRIDAE.
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 HEPATITIS A VIRUS
TRANSMISSION
• Close personal contact (e.g. household contact,
child day care centers).
• Contaminated food & water (e.g. infected food
handlers, raw shellfish).
• Its spread is aided by overcrowding, poor personal,
environmental hygiene and sanitation.
• Blood exposure (very rare) (e.g. injection drug use,
transfusion).

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 PATHOGENESIS – HAV
Cause sub-acute disease in children & young
adults.
HAV invade into human body by fecal - oral
route,
route multiplies in the intestinal epithelium &
reaches the liver by hematogenous spread.
After one week, the HAV reach liver cells
replicate within. Then enter intestine with bile
and appear in feces.
Incubation Period:
Period 2 to 6 weeks (15 - 50 days).
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 PATHOGENESIS – HAV
After HAV replicating and discharging, liver
cells damage begin.
HAV is not cytopathic for hepatocytes; cell
death is brought about by T cell-mediated
mechanisms directed at infected liver cells.
Mortality is < 1 per 1000 and less than 1%
present with the fulminant hepatic failure picture.
HAV typically causes acute self-limited
disease and virtually all patients recover
completely and without any chronic sequelae.

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 LABORATORY DIAGNOSIS

1. DEMONSTRATION OF VIRUS IN FECES: FECES

By: Immunoelectromicroscopy.
Molecular Diagnosis: RT PCR of feces.
2. VIRUS ISOLATION
3. The most reliable assay for the diagnosis of
acute HAV is the detection of HAV-
specific IgM in serum.

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 HEPATITIS A VACCINATION
Vaccines against HAV were only licensed within the
last decade or so.
There are 2 types:
•Formaldehyde-inactivated.
•The live-attenuated vaccines.
Many cases occur in community-wide outbreaks:
– No risk factor identified for most cases.
– Highest attack rates in 5-14 year olds.
– Children serve as reservoir of infection.

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HEPATITIS B VIRUS

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 PROPERTIES OF HBV
• A member of the hepadnavirus group.
• Circular partially double-stranded
DNA viruses.
• 42nm enveloped virus.
• Endemic in the human population
and hyper-endemic in many parts
of the world.
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HBV: STRUCTURE

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HBV STRUCTURE & ANTIGENS
DANE
PARTICLE

HBsAg = surface (coat) protein.

HBcAg = inner core protein.
HBeAg = secreted protein; an indicator of
 The genome of HBV is made
up of DNA molecule with 3200 that
encodes four (4) proteins:
•Two (2) non-structural proteins (X
and DNA polymerase) that are
involved in viral replication.
•Two (2) structural proteins (core
and surface antigens).
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 The functions of the non-structural
proteins are:
•The DNA Polymerase gene with reverse
transcriptase encode the viral enzymes
that are necessary for HBV replication.
•The proteins encoded by the X (trans-
activating) gene have been found to play a
role in causation of hepatocellular
carcinoma by p53 degradation and
expression.

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 The structural genes functions:
• The surface gene encodes 3 proteins that
have a common carboxy terminus and an
amino terminus of variable length.
• These three surface proteins can aggregate
to form non-infectious particles lacking
HBV DNA and known as HbsAg.
• Alternatively, they can form the envelope of
complete infectious virions known as the
DANE PARTICLE.

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 DECOY PARTICLES

HBsAg-containing
particles are released
into the serum of
infected people and
outnumber the actual
virions.
Spherical / filamentous.

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• They are immunogenic and
were processed into the first
commercial vaccine against
HBV.
• The role of HbsAg is thought
to serve as a decoy for virus-
neutralising anti-envelope
antibodies.
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 The core gene contains 2 start
codons:
•Translation from the 1st codon
leads to the formation of a pre-
core/core protein (HBcAg).
•Translation from the 2nd codon
leads to the formation of the viral
nucleocapsid protein core
(HBeAg).
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 HBcAg is retained in the
infected hepatocytes,
while the HBeAg is
secreted into blood and is
essential for the
establishment of
persistent infection.
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 HBV: REPLICATION
• Reverse transcription: one of the mRNAs is
replicated with a reverse transcriptase making
the DNA that will eventually be the core of the
progeny virion.
• RNA intermediate: HBV replicates through an
RNA intermediate and produces and release
antigenic decoy particles.
• Integration: Some DNA integrates into host
genome causing carrier state.
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Replication of HBV

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 HBV:
MODES OF TRANSMISSION
 Parenteral - IV drug abusers, health
workers are at increased risk.
 Sexual - sex workers & homosexuals
are particular at risk.
 Perinatal (Vertical) – mother
(HBeAg ) → infant.
+

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 EPIDEMIOLOGY

• 350,000,000 carriers worldwide.

• 15 to 25% of chronically infected
patients will die from chronic
liver disease.

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 Prevalence of chronic HBV carriers

Percentage chronic HBsAg carriers:

< 2% - Low
2-7% - Intermediate
> 8% - High Margolis et al, 1991
 CONCENTRATION OF HEPATITIS B
VIRUS IN VARIOUS BODY FLUIDS

LOW/NOT
HIGH MODERATE DETECTABLE

blood semen urine

feces
serum vaginal fluid
sweat
wound exudates saliva tears
Breast milk

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 HIGH – RISK GROUPS FOR
HBV INFECTION

• People from endemic regions.

• Babies of mothers with chronic HBV.
• Intravenous drug abusers.
• People with multiple sex partners.
• Hemophiliacs and other patients requiting blood and
blood product treatments.
• Health care personnel who have contact with blood.

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 ACUTE HEPATITIS B VIRUS INFECTION WITH
RECOVERY
Symptoms
Typical Serologic Course
HBe Ag anti- HBe

Total anti- HBc

Titre

HBs Ag IgM anti- HBc anti- HBs

0 4 8 12 16 20 24 28 32 36 52 100
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Weeks after Exposure
 PATHOGENESIS & IMMUNITY
• Virus enters hepatocytes via blood and replicate.
• Immune response (cytotoxic T cell) to viral antigens
expressed on hepatocyte cell surface responsible
for clinical syndrome.
• 5% become chronic carriers (HBsAg > 6 months).
• Higher rate of hepatocellular cancer in chronic
carriers, especially those who are “e” antigen
positive.
• Hepatitis B surface antibody likely confers lifelong
immunity (IgG anti-HBs).
• Hepatitis Be Ab indicates low transmissibility.

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HBV is not normally directly
cytopathic to hepatocytes.
Liver cell death is achieved
through HLA-restricted CTL
mediated cell death of virus-
infected cells.
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 CLINICAL FEATURES
Incubation period: Average 60-90 days
Range 45-180 days
Insidious onset of symptoms tends to cause a more severe disease than
Hepatitis A.
Clinical illness (jaundice): <5 yrs - <10%
≥ 5 yrs - 30%-50%
1/3 adults-no symptoms
Clinical illness at presentation 10 - 15%
Acute case-fatality rate: 0.5%-1%
Chronic infection: < 5 yrs - 30%-90%
≥ 5 yrs - 2%-10%
More likely in asymptomatic infections
Premature mortality from
chronic liver disease: 15%-25%

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 Possible outcomes of infection
with hepatitis B virus
Transient
Subclinical 65%
100%
Infection
Acute Chronic
HBV 10% Infection
Recovery
Infection
99% 25%
Acute
Hepatitis
1%
Fulminant
Hepatitis

Death Adapted from Feitelson, 1994

LABORATORY DIAGNOSIS
 DIAGNOSIS
Serological tests used for the diagnosis of acute and chronic hepatitis B
infection:
•HBsAg: used as a general marker of infection.
•HBsAb: used to document recovery and / or immunity to HBV infection.
infection
•Anti-HBc IgM: marker of acute infection.
•Anti-HBc IgG: past or chronic infection.
•HBeAg: indicates active replication of virus and therefore infectiveness.
•Anti-Hbe: virus no longer replicating.
replicating However, the patient can still be
positive for HBsAg.
•HBV-DNA: indicates active replication of virus, more accurate than
HBeAg especially in cases of escape mutants. Used mainly for
monitoring response to therapy.

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 PREVENTION
• Vaccination: highly effective recombinant vaccines are now
available. Vaccine can be given to those who are at increased
risk of HBV infection such as health care workers. It is also
given routinely to neonates as universal vaccination in many
countries.
• Hepatitis B Immunoglobulin: HBIG may be used to protect
persons who are exposed to hepatitis B. It is particular
efficacious within 48 hours of the incident. It may also be
given to neonates who are at increased risk of contracting
hepatitis B i.e. whose mothers are HBsAg and HBeAg positive.
• Other measures: screening of blood donors, blood and body
fluid precautions.

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 HEPATITIS B VACCINE
• Infants: several options that depend on status of the
mother:
– If mother HBsAg negative: birth, 1-2 months, 6-18 months.
– If mother HBsAg positive: vaccine & Hepatitis B immune
globulin within 12 hours of birth, 1-2months, <6 months.
• Adults:
– 0,1, 6 months.
• Vaccine recommended in:
– All those aged 0-18.
– Those at high risk.

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HEPATITIS C VIRION: SPHERICAL, ICOSAHEDRAL,
NUCLEIC ACID: SS (+) RNA
Genome resembled that of a flavivirus positive stranded RNA genome of around
10,000 bases.
 eplicates exclusively in the cytop
replicates
via an RNA intermediate
Viral entry & uncoating

(+) Translation & processing

(+)

(-)
HCV RNA
Virus particle replication
assembly Replicative
intermediate
(+)

Nucleus
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 HEPATITIS C – CLINICAL FEATURES

Incubation period: Average 6-7

weeks.
Range 2-26 weeks.

Clinical illness (jaundice): 30-40% (20-30%).

Chronic hepatitis: 70%.

Persistent infection: 85-100%.

Immunity: No protective
antibody response
CHRONIC HEPATITIS C INFECTION
• About 85% of individuals acutely infected
with HCV become chronically infected.
Hence, HCV is a major cause of chronic
hepatitis.
• About 20% of individuals with hepatitis C
who do develop cirrhosis will develop end-
stage liver disease and are at an increased
risk of developing hepatocellular
carcinoma.
• One fairly clear factor for progression to
cirrhosis is concurrent alcohol abuse.
 HEPATITIS C VIRUS INFECTION
Typical Serologic Course
anti-
HCV
Symptoms

Titre

ALT

Normal

0 1 2 3 4 5 6 1 2 3 4
Months Years
Time after Exposure
 RISK FACTORS ASSOCIATED WITH
TRANSMISSION OF HCV
 Transfusion or transplant from infected donor.
 Injecting drug use.
 Hemodialysis (years on treatment).
 Accidental injuries with needles / sharps.
 Sexual / household exposure to anti-HCV-positive
contact.
 Multiple sex partners.
 Birth to HCV-infected mother.

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 LABORATORY DIAGNOSIS
• HCV ANTIBODY: generally used to diagnose hepatitis C
infection. Not useful in the acute phase as it takes at least 4 weeks
after infection before antibody appears.
• HCV-RNA: various techniques are available e.g. PCR and
branched DNA. May be used to diagnose HCV infection in the
acute phase. However, its main use is in monitoring the response
to antiviral therapy.
• HCV-ANTIGEN: an EIA for HCV antigen is available. It is used
in the same capacity as HCV-RNA tests but is much easier to carry
out.

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OUTCOMES OF HCV HEPATITIS
PREVENTION OF HEPATITIS
C
 Screening of blood, organ, tissue
donors.
 High-risk behavior modification.

 Blood and body fluid precautions.

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 HEPATITIS D VIRUS
• The delta agent is a defective virus which
consists of a particle 35 nm in diameter
consisting of the delta antigen surrounded by
an outer coat of HBsAg.
• The genome of the virus is very small and
consists of a single-stranded RNA.
• The hepatitis D virus is replication defective
and therefore cannot propagate in the
absence of another virus.
• In humans, hepatitis D virus infection only
occurs in the presence of hepatitis B
HEPATITIS D (DELTA) VIRION

From Murray et. al., Medical

Microbiology 5th edition, 2005,
Chapter 66, published by Mosby
Philadelphia,,
 A patient can acquire hepatitis D
virus infection at the same time as
he/she is infected with the hepatitis
B virus.
virus This is called co-infection.
co-infection
A patient with hepatitis B can be
infected with hepatitis D virus at
any time after acute hepatitis B
virus infection.
infection This is called super-
infection.
infection
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 CONSEQUENCES OF HEPATITIS B AND
DELTA VIRUS INFECTION

Consequences of delta virus infection. Delta virus (d) requires the presence of hepatitis B virus (HBV)
infection. Super infection of a person already infected with HBV (carrier) causes more rapid, severe
progression than co-infection (shorter arrow).

From Murray et. al., Medical Microbiology 5th edition, 2005, Chapter 66, published by Mosby Philadelphia.

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HEPATITIS D VIRUS MODES OF
TRANSMISSION
 Percutaneous exposures.
 Injecting drug use.
 Permucosal exposures.
 Sex contact.
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 HEPATITIS D: CLINICAL
FEATURES
 CO-INFECTION:
– Severe acute disease.
– Low risk of chronic infection.
 SUPER-INFECTION:
– Usually develop chronic HDV infection.
– High risk of severe chronic liver disease.
– May present as an acute hepatitis.

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 LABORATORY DIAGNOSIS

Co-infection or super-infection with

hepatitis D virus in a patient with
hepatitis B is diagnosed by the
presence of antibodies against
the hepatitis D virus.
The gold standard for diagnosis is
Liver tissue immunohistochemistry.
immunohistochemistry

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 HBV - HDV COINFECTION
Typical Serologic Course
Symptoms

ALT Elevated

Titre
anti-HBs
IgM anti-
HDV

HDV RNA

HBsAg
Total anti-HDV

Time after 60
HBV – HDV SUPERINFECTION
Typical Serologic Course
Jaundice

Symptoms

Total anti-HDV
ALT
Titre

HDV RNA
HBsAg

IgM anti-HDV

Time after Exposure 61

HEPATITIS D – PREVENTION
 HBV-HDV CO-INFECTION:
Pre or post exposure prophylaxis to prevent
HBV infection.
 HBV-HDV SUPER-INFECTION:
Education to reduce risk behaviors among
persons with chronic HBV infection.

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 HEPATITIS E VIRUS

• Is a feco-oral transmitted, waterborne

infection.
• It is an unenveloped RNA virus, 32-34nm
in diameter.
• +ve stranded RNA genome, 7.6 kb in
size.
• Very labile and sensitive.
• Can only be cultured recently.
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 The clinical course of HEV
infection is very similar to that of
the HAV.
About 30% of patients develop
cholestatic jaundice, which in
healthy adults is a mild disease.
However, in pregnant women up
to 20% of patients develop a
fatal, fulminant hepatitis.
 HEPATITIS E - CLINICAL
FEATURES
 Incubation period: Average 40 days.
Range 15 - 60 days.
 Case-fatality rate: Overall, 1%-3%.
Pregnant women,
15%-25%.
 Illness severity: Increased with age.
 Chronic sequelae: None identified.
 HEPATITIS E VIRUS INFECTION
Typical Serologic Course
Symptom
s

ALT IgG anti-HEV

Titer IgM anti-HEV

Virus in stool

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Weeks after Exposure

 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.
 Minimal person-to-person transmission.
 Prevention and Control Measures for
Travelers to HEV-Endemic Regions
 Avoid drinking water (and beverages with ice) of
unknown purity, uncooked shellfish, and
uncooked fruit/vegetables not peeled or prepared
by traveler.
 IG prepared from donors in Western countries
does not prevent infection.
 Unknown efficacy of IG prepared from donors in
endemic areas.
 Vaccine????
 HEPATITIS G VIRUS

FLAVIRUS: similar morphology and

genome
◊ In risk groups: acute, chronic and
fulminant hepatitis.
◊ ? transmission: blood (mother- newborn
babies)
◊ ? prevalence is higher in HCV infected
people
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Prodromal or Pre-icteric phase:
Symptoms: fatigue, joint and abdominal
pain, malaise, vomiting, lack of appetite,
hepatomegaly.
Icteric phase:
Icterus: jaundice (skin, sclera, mucous
membranes) cause: elevated bilirubin level,
bilirubinuria: dark urine, pale stool.

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THANK YOU
FOR
LISTENING
SEYEADENIRAN@GMAIL.COM

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