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Hepatitis A and B. Dr. Amanj Saeed MBCHB, MSc, PhD [email protected]. Clinical Features of Viral Hepatitis. PreictericMalaise Anorexia Nausea Abdominal discomfort Pyrexia (fever) IctericPale stool/dark urine Jaundice. Hepatitis A Virus. - PowerPoint PPT Presentation
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Clinical Features of Clinical Features of Viral HepatitisViral Hepatitis
Preicteric Malaise
Anorexia
Nausea
Abdominal discomfort
Pyrexia (fever)
Icteric Pale stool/dark urine
Jaundice
Hepatitis A VirusHepatitis A VirusRNA genome, +ve single stranded RNARNA genome, +ve single stranded RNA
7.5 kb in length encodes for polypeptides 7.5 kb in length encodes for polypeptides VP1, VP2, VP3, and VP4. VP1, VP2, VP3, and VP4.
Little is known about mechanism of entery Little is known about mechanism of entery
Genome multiplication occurs in cytoplasm.Genome multiplication occurs in cytoplasm.
The genome can act as messenger RNA The genome can act as messenger RNA directlydirectly
The incoming viral RNA strand directs the The incoming viral RNA strand directs the synthesis of a large viral polyprotein, which synthesis of a large viral polyprotein, which is then cleaved in to segments. is then cleaved in to segments.
Hepatitis A VirusHepatitis A VirusTranslation of RNA dependent RNA Translation of RNA dependent RNA polymerase is crucial stem of viral life cycle. polymerase is crucial stem of viral life cycle.
Initial step is viral RNA replication is to copy Initial step is viral RNA replication is to copy the incoming genome to form the incoming genome to form complementary negative strand. , which complementary negative strand. , which serves as a template for synthesis of serves as a template for synthesis of positive genome RNA. positive genome RNA.
The assembly is complex and require The assembly is complex and require maturation cleavage of the structural maturation cleavage of the structural proteins. proteins.
Transmission and Transmission and clinical clinical
manefestation manefestation Faeco-oral route of transmissionFaeco-oral route of transmission Entry via contaminated food or waterEntry via contaminated food or water Excreted in faeces Excreted in faeces Blood and blood products, needle, and sexual contact. Blood and blood products, needle, and sexual contact.
The incubation period is 2-6 weeks.The incubation period is 2-6 weeks.
Many infections are silent Many infections are silent
Clinical features:Clinical features: Malase Malase Loss of appetite Loss of appetite Vague abdominal discomfort Vague abdominal discomfort Fever Fever Dark urine and pale faeces Dark urine and pale faeces Jaundice (first in sclera and then skin)Jaundice (first in sclera and then skin) Itching in severe cases Itching in severe cases
Transmission and Transmission and clinical clinical
manefestation manefestation Hepatitis A is self limiting Hepatitis A is self limiting
Recurrence is reported Recurrence is reported
Less severe in children Less severe in children
1/1000 fulminant hepatitis (rare)1/1000 fulminant hepatitis (rare)
Pathology Pathology HAV replicate in hepatocyte .HAV replicate in hepatocyte .
Shed in large quantities in the faeces Shed in large quantities in the faeces
Hepatitis A Virus – Hepatitis A Virus – Consequences of Consequences of
InfectionInfectionAsymptomatic infectionAsymptomatic infection
Acute icteric hepatitisAcute icteric hepatitis
Fulminant hepatitis (rare)Fulminant hepatitis (rare)
Necrosis of hepatocyte Necrosis of hepatocyte
Proliferation of kupffer and other Proliferation of kupffer and other endothelial cellsendothelial cells
Elevated liver enzyme Elevated liver enzyme
No chonicity, cirrhosis or malignant change No chonicity, cirrhosis or malignant change
Immunity to HAV Immunity to HAV Specific IgM in prodromal phase Specific IgM in prodromal phase
IgG neutralizing antibody is detectable IgG neutralizing antibody is detectable for many years.for many years.
Diagnosis Diagnosis Liver function test (raised serum Liver function test (raised serum Bilirubin and transaminases) Bilirubin and transaminases)
Depressed prothrombin level Depressed prothrombin level
Elisa for specific IgMElisa for specific IgM
Immunisation Immunisation Human normal immunoglobulin Human normal immunoglobulin
Formalin inactivated vaccine. Formalin inactivated vaccine.
HBV HBV 350-360 million people chronically 350-360 million people chronically Infected worldwide.Infected worldwide.
Dandri and Stephen LocarniniDandri and Stephen Locarnini, , New insight in the pathobiology New insight in the pathobiology of hepatitis B virus infection, Gut, April 2012. of hepatitis B virus infection, Gut, April 2012.
In europe 950 000 cases every year, 90 In europe 950 000 cases every year, 90 000 become carriers, 19 000 die of liver 000 become carriers, 19 000 die of liver cirrhosis and 5000 die of liver cancer.cirrhosis and 5000 die of liver cancer.
In US 200 000 new cases per year In US 200 000 new cases per year
Hepatitis B Virus (HBV)
• Discovered in 1965 (Blumberg et al)
• Hepadnavirus (DNA)
Source: Center for Disease Control and Prevention
DNA
Core Ag
Also eAg
Surface Ag
• Circular, partly double-stranded DNA
The HBV genome
• Very compact and contains 4 overlapping open reading frames (ORFs)
• Minus strand of viral DNA is 3.2kb
• Plus strand is shorter and variable in size (1.8 to 2.7kb)
• 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 Morphology Different shape Different shape
Some are 42 nm in diameter and double shelled Some are 42 nm in diameter and double shelled
others are 20-22 nm in diameter.others are 20-22 nm in diameter.
Complete virion some times called Dane particleComplete virion some times called Dane particle
The nucleocapsid contain:The nucleocapsid contain:
The DNA genomeThe DNA genome
DNA dependent DNA polymerase DNA dependent DNA polymerase
HB core antigen (HBcAg)HB core antigen (HBcAg)
HB e antigen (HBeAg)HB e antigen (HBeAg)
Genome Genome Compact genome Compact genome
Circular ds DNA Circular ds DNA
32 kbp in size 32 kbp in size
4 overlapping open reading frame ORF.4 overlapping open reading frame ORF.
The virus encode 50% more protein The virus encode 50% more protein than expected.than expected.
Replication Replication The virus attaches to hepatocyte using the The virus attaches to hepatocyte using the virion S protein ( candidate receptors include virion S protein ( candidate receptors include transferrin receptor, the asialoglycoprotien transferrin receptor, the asialoglycoprotien receptor molecule, and human liver endonexin) receptor molecule, and human liver endonexin)
The virus enters by endocytosis The virus enters by endocytosis
Virus nucleocapsid moves to the nucleus Virus nucleocapsid moves to the nucleus
Enters cell as partially ds DNAEnters cell as partially ds DNA
22ndnd strand is completed strand is completed covalently closed covalently closed circular DNA (cccDNA) (mini chromosome)circular DNA (cccDNA) (mini chromosome)
The minus strand is transcribed to give mRNA The minus strand is transcribed to give mRNA with a 3.4 kb RNA transcript called with a 3.4 kb RNA transcript called (pregenome)(pregenome)
Replication Replication Mode of genome replication is unusual Mode of genome replication is unusual include reverse transcription of DNA from include reverse transcription of DNA from RNA intermediateRNA intermediate
RT is lack of proofreading leading to high RT is lack of proofreading leading to high mutation rate.mutation rate.
Mutation occur is pre S region which is Mutation occur is pre S region which is important for viral attachment and entry.important for viral attachment and entry.
The new enveloped viruses emerge The new enveloped viruses emerge without cell lysis.without cell lysis.
Use of Reverse Use of Reverse TranscriptaseTranscriptase
HBV DNA
mRNA
Translation
Viral proteins: HBsAgHBcAgHBeAgReverse Transcriptase
The main The main antigens antigens
HBsAgHBcAgHBeAgEach 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 Subtypes and genotypesgenotypes
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 Clinical presentation presentation
Clinical features are variable and related to:
Age Sex State of immune system.Genotype of the virus
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 - Adults
subclinical hepatitis icteric hepatitis (jaundice) Acute infection fulminant hepatitis chronic infection (90%) healthy carrier chronic cirrhosis hepatitis Ca liver
Natural History of HBV Infection - Neonates
Clinical features Clinical features Prodromal phase similar to that of HAVProdromal phase similar to that of HAV
Rash and arthropathyRash and arthropathy
Jaundice Jaundice
Chronic infection (5-10% in adults)Chronic infection (5-10% in adults)
HBV antigen and HBV antigen and antibody antibody
appearance appearance Increased serum amylase Increased serum amylase
Detectible HBsAgDetectible HBsAg
Followed by appearance of HBeAg and DNA Followed by appearance of HBeAg and DNA polymerase polymerase
The first antibody to appear is anti- HBcThe first antibody to appear is anti- HBc
Followed by appearance of anti-HBe (good Followed by appearance of anti-HBe (good prognostic sign) prognostic sign)
Anti HBs is the last antibody to appear and Anti HBs is the last antibody to appear and indicate full recovery and immunity to the indicate full recovery and immunity to the virus.virus.
Clinical outcome Clinical outcome
• Perinatal (mother to baby at the birth)
• Sexual
• Parenteral (unsafe injections and
transfusion)
•Other body fuids??
Hepatitis B Virus
Modes of TransmissionHepatitis B Virus
Modes of Transmission
Acute hepatitis BAcute hepatitis B
HBsAg positive
anti-HBc positive
Acute infection will either resolve or become chronic
Resolved acute HBV Resolved acute HBV infection 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 Chronic HBV infectioninfection
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 Diagnosis
ELISA Reverse passive haemagglutination Latex slide testDetection of viral DNA and DNA polymerase EM
Treatment 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 Prevention of HBV infectioninfection
Simple precautionsSimple precautions
Hepatitis B immunoglobulin (passive Hepatitis B immunoglobulin (passive immunisation)immunisation)
Hepatitis B vaccine (active Hepatitis B vaccine (active immunisation)immunisation)
Immunisation Immunisation Vaccine (20 ug of HBsAg given IM at 0, Vaccine (20 ug of HBsAg given IM at 0, 1, and 6 months. With booster dose at 5 1, and 6 months. With booster dose at 5 year intervals for those at special riskyear intervals for those at special risk
Immunoglobulin Immunoglobulin
Who should be Who should be vaccinated?vaccinated?
Universal vaccination?Universal vaccination?
Selective vaccination?Selective vaccination?