1. Hepatitis A and B
Dr. Amanj Saeed
MBCHB, MSc, PhD

2. Clinical Features of Viral Hepatitis
Preicteric Malaise
Anorexia
Nausea
Abdominal discomfort
Pyrexia (fever)
Icteric Pale stool/dark urine
Jaundice

6. 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.

7. 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.

8. 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

9. Transmission and clinical manefestation
Hepatitis A is self limiting
Recurrence is reported
Less severe in children
1/1000 fulminant hepatitis (rare)

10. Pathology HAV replicate in hepatocyte .
Shed in large quantities in the faeces

13. 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

14. Immunity to HAV Specific IgM in prodromal phase
IgG neutralizing antibody is detectable for many years.

15. Diagnosis
Liver function test (raised serum Bilirubin and transaminases)
Depressed prothrombin level
Elisa for specific IgM

16. Immunisation
Human normal immunoglobulin
Formalin inactivated vaccine.

17. 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 cases every year, become carriers, die of liver cirrhosis and 5000 die of liver cancer.
In US new cases per year

18. Hepatitis B Virus (HBV)
Surface Ag
Discovered in 1965 (Blumberg et al)
Hepadnavirus (DNA)
Source: Center for Disease Control and Prevention
Core Ag
Also eAg
DNA

19. 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)

20. Morphology Different shape
Some are 42 nm in diameter and double shelled
others are 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)

21. Genome Compact genome Circular ds DNA 32 kbp in size
4 overlapping open reading frame ORF.
The virus encode 50% more protein than expected.

22. 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)

23. 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.

24. Use of Reverse Transcriptase
HBV DNA
mRNA
Translation
Viral proteins:
HBsAg
HBcAg
HBeAg
Reverse Transcriptase

25. 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.

26. 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

27. Clinical presentation
Clinical features are variable and related to:
Age
Sex
State of immune system.
Genotype of the virus

28. Natural History of HBV Infection - Adults

29. Natural History of HBV Infection - Neonates

31. Clinical features Prodromal phase similar to that of HAV
Rash and arthropathy
Jaundice
Chronic infection (5-10% in adults)

32. 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.

33. 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.

34. Perinatal (mother to baby at the birth) Sexual
Hepatitis B Virus
Modes of Transmission
Perinatal (mother to baby at the birth)
Sexual
Parenteral (unsafe injections and transfusion)
Other body fuids?? 2 2 2

35. Acute hepatitis B HBsAg positive anti-HBc positive
Acute infection will either resolve or become chronic

36. 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

37. 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 ….)

38. Diagnosis ELISA Reverse passive haemagglutination Latex slide test
Detection of viral DNA and DNA polymerase EM

39. 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

40. Prevention of HBV infection
Simple precautions
Hepatitis B immunoglobulin (passive immunisation)
Hepatitis B vaccine (active immunisation)

41. 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

42. Who should be vaccinated?
Universal vaccination?
Selective vaccination?