Transcript Hepatitis A and B

Hepatitis A and B
Dr. Amanj Saeed
MBCHB, MSc, PhD
[email protected]
Clinical Features of Viral
Hepatitis
Preicteric
Malaise
Anorexia
Nausea
Abdominal discomfort
Pyrexia (fever)
Icteric
Pale stool/dark urine
Jaundice
Hepatitis A Virus
RNA genome, +ve single stranded RNA
7.5 kb in length encodes for polypeptides VP1, VP2, VP3,
and VP4.
Little is known about mechanism of entery
Genome multiplication occurs in cytoplasm.
The genome can act as messenger RNA directly
The incoming viral RNA strand directs the synthesis of a
large viral polyprotein, which is then cleaved in to
segments.
Hepatitis A Virus
Translation of RNA dependent RNA polymerase is
crucial stem of viral life cycle.
Initial step is viral RNA replication is to copy the
incoming genome to form complementary negative
strand. , which serves as a template for synthesis of
positive genome RNA.
The assembly is complex and require maturation
cleavage of the structural proteins.
Transmission and clinical
manefestation
 Faeco-oral route of transmission
 Entry via contaminated food or water
 Excreted in faeces
 Blood and blood products, needle, and sexual contact.
 The incubation period is 2-6 weeks.
 Many infections are silent
 Clinical features:
 Malase
 Loss of appetite
 Vague abdominal discomfort
 Fever
 Dark urine and pale faeces
 Jaundice (first in sclera and then skin)
 Itching in severe cases
Transmission and clinical
manefestation
Hepatitis A is self limiting
Recurrence is reported
Less severe in children
1/1000 fulminant hepatitis (rare)
Pathology
HAV replicate in hepatocyte .
Shed in large quantities in the faeces
Hepatitis A Virus –
Consequences of Infection
Asymptomatic infection
Acute icteric hepatitis
Fulminant hepatitis (rare)
Necrosis of hepatocyte
Proliferation of kupffer and other endothelial cells
Elevated liver enzyme
No chonicity, cirrhosis or malignant change
Immunity to HAV
Specific IgM in prodromal phase
IgG neutralizing antibody is detectable for many
years.
Diagnosis
Liver function test (raised serum Bilirubin and
transaminases)
Depressed prothrombin level
Elisa for specific IgM
Immunisation
Human normal immunoglobulin
Formalin inactivated vaccine.
HBV
350-360 million people chronically Infected
worldwide.
Dandri and Stephen Locarnini, New insight in the pathobiology of hepatitis B
virus infection, Gut, April 2012.
In europe 950 000 cases every year, 90 000 become
carriers, 19 000 die of liver cirrhosis and 5000 die of liver
cancer.
In US 200 000 new cases per year
Hepatitis B Virus (HBV)
Surface Ag
• Discovered in 1965 (Blumberg et al)
• Hepadnavirus (DNA)
Core Ag
Also eAg
DNA
Source: Center for Disease Control and Prevention
The HBV genome
• Circular, partly double-stranded DNA
• Minus strand of viral DNA is 3.2kb
• Plus strand is shorter and variable in size
(1.8 to 2.7kb)
• Very compact and contains 4 overlapping open reading frames (ORFs)
• Upon entry into a liver cell, the viral core particle is translocated into the
nucleus of the cell, the viral DNA is then repaired and matured by a virion
DNA polymerase, giving rise to Covalently Closed Circular DNA (cccDNA)
Morphology
 Different shape
 Some are 42 nm in diameter and double shelled
 others are 20-22 nm in diameter.
 Complete virion some times called Dane particle
The nucleocapsid contain:
The DNA genome
DNA dependent DNA polymerase
HB core antigen (HBcAg)
HB e antigen (HBeAg)
Genome
Compact genome
Circular ds DNA
32 kbp in size
4 overlapping open reading frame ORF.
The virus encode 50% more protein than expected.
Replication
The virus attaches to hepatocyte using the virion S protein (
candidate receptors include transferrin receptor, the
asialoglycoprotien receptor molecule, and human liver
endonexin)
The virus enters by endocytosis
Virus nucleocapsid moves to the nucleus
Enters cell as partially ds DNA
2nd strand is completed  covalently closed circular DNA
(cccDNA) (mini chromosome)
The minus strand is transcribed to give mRNA with a 3.4 kb
RNA transcript called (pregenome)
Replication
Mode of genome replication is unusual include
reverse transcription of DNA from RNA intermediate
RT is lack of proofreading leading to high mutation
rate.
Mutation occur is pre S region which is important for
viral attachment and entry.
The new enveloped viruses emerge without cell lysis.
Use of Reverse
Transcriptase
HBV DNA
mRNA
Translation
Viral proteins:
HBsAg
HBcAg
HBeAg
Reverse Transcriptase
The main antigens
 HBsAg
 HBcAg
 HBeAg
 Each HBV Ag stimulate corresponding antibodies
 All HBV Ag and Ab (except HBcAg) together with the
viral DNA polymerase can be detect in the blood at
various times after infection.
 HBc Ag can only be detected in the hepatocyte nuclei.
Subtypes and
genotypes
 Surface antigen determine serological
specificities to determine subtype of HBV.
 DNA sequencing
 Genetic analysis revealed 7 genotype of the
virus with %8 nucleotyde sequence difference
differences
 Useful for epidemiological studies
Clinical presentation
Clinical features are variable and related to:
 Age
 Sex
 State of immune system.
 Genotype of the virus
Natural History of HBV
Infection - Adults
subclinical hepatitis
icteric hepatitis (jaundice)
Acute infection
fulminant hepatitis
chronic infection (5-10%)
healthy carrier chronic cirrhosis
hepatitis
Ca liver
Natural History of HBV
Infection - Neonates
subclinical hepatitis
icteric hepatitis (jaundice)
Acute infection
fulminant hepatitis
chronic infection (90%)
healthy carrier chronic cirrhosis
Ca liver
hepatitis
Clinical features
Prodromal phase similar to that of HAV
Rash and arthropathy
Jaundice
Chronic infection (5-10% in adults)
HBV antigen and
antibody appearance
Increased serum amylase
Detectible HBsAg
Followed by appearance of HBeAg and DNA polymerase
The first antibody to appear is anti- HBc
Followed by appearance of anti-HBe (good prognostic
sign)
Anti HBs is the last antibody to appear and indicate full
recovery and immunity to the virus.
Clinical outcome
1:1000 of case may develop fulminant hepatitis.
10 become chronic infection:
chronic antigenaemia: patient fail to form anti HBs
and delayed anti Hbe. HBsAg persist in blood, patient
is well, liver function is normal.
Chronic active (aggressive) hepatitis: patient fail to
produce anti HBs and anti Hbe, they carry HBsAg and
infectious virion, become infectious to others, liver
damage and impaired liver function, epesodes of
hepatitis and eventually cirrhosis.
HCC: occur as a result of integration of viral genome
to the DNA of hepatocyte.
Hepatitis B Virus
Modes of Transmission
• Perinatal (mother to baby at the birth)
• Sexual
• Parenteral (unsafe injections and
transfusion)
• Other body fuids??
Acute hepatitis B
HBsAg positive
anti-HBc positive
Acute infection will either resolve or become
chronic
Resolved acute HBV
infection
HBsAg disappears (may take up to 6 months
Serum becomes positive for
anti-HBc (IgG) - is therefore a marker of past
infection
anti-HBs - may also arise as a result of
vaccination
Chronic HBV infection
Defined as persistence of HBsAg for > 6 months
(i) HBeAg positive
- high infectivity eg needlestick
- increased risk of inflammatory liver disease
(ii) Anti-HBe positive
- low infectivity (but …..)
- low risk of CLD (but ….)
Diagnosis
 ELISA
 Reverse passive haemagglutination
 Latex slide test
 Detection of viral DNA and DNA polymerase
 EM
Treatment
 Acute infection does not normally require
treatment
 HBeAg positive carrier demand treatment



INF-α (6-10 MU three times weekly reduce viral load,
HBsAg and HBeAg.
Lamivudine and Famciclovir
adefovir
Prevention of HBV
infection
Simple precautions
Hepatitis B immunoglobulin (passive immunisation)
Hepatitis B vaccine (active immunisation)
Immunisation
Vaccine (20 ug of HBsAg given IM at 0, 1, and 6
months. With booster dose at 5 year intervals for
those at special risk
Immunoglobulin
Who should be vaccinated?
Universal vaccination?
Selective vaccination?