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Hepatitis viruses

Cause systemic disease primarily involving liver
Caused by
  1. Hepatitis A virus               
  2. Hepatitis B virus           
  3. Hepatitis C virus
  4. Hepatitis D virus             
  5. Hepatitis E virus   
Other viruses that can cause sporadic hepatitis are:
  1. Yellow fever virus             
  2. Cytomegalovirus          
  3. Epstein-Barr virus           
  4. Herpes simplex virus           
  5. Enteroviruses
a. Hepatitis A virus
  • Member of Picornaviridae
  • Previously classified as enterovirus 72
  • Now assigned to new genus Hepatovirus
  • 27nm, icosahedral, linear, single stranded RNA, linear, positive polarity, nonenveloped
  • Only one serotype exists
  • One of the most stable viruses infecting humans
  • Only one of the human hepatitis viruses that can be cultivated in vitro
i. Pathogenesis
  • Virus is shed in the stools of infected persons
  • Infection is transmitted by feco-oral route
  • First multiplies in the intestinal epithelial cells→ spreads to the liver via blood
  • Accounts for 25% of acute hepatitis cases world wide
ii. Clinical features
  • Acute self limiting disease, I.P.: 2-6 weeks
  • Abrupt onset with fever, malaise, anorexia, nausea, lethargy followed by jaundice and hepatomegaly
  • Less than 0.5% cases develop fulminant hepatitis
  • Complete recovery in 8-12 weeks Severity of the disease varies with the age
  • 5% children < 3 years develop jaundice
  • >50% of the adults develop jaundice
  • No extra hepatic manifestation, no carrier state
  • Not associated with cirrhosis/ hepatocellular carcinoma
iii. Laboratory diagnosis
  • Raised AST& ALT
  • Demonstration of virus particles: immunoelectron microscopy
  • Antigen detection: ELISA
  • Serology: IgM antibodies, ELISA
  • Isolation: tissue culture
  • Nucleic acid detection: PCR
iv. Prophylaxis: Killed vaccine available
b. Hepattis B virus
i. Family: Hepadnaviridae
  • Consists of Hepatitis viruses of humans (HBV) and animals
ii. Morphology
  • Hepatitis B virus/ Dane particle42 nm, envelop contains hepatitis B surface antigen (HBsAg). It encloses an inner icosahedral 27nm nucleocapsid. It contains Hepatitis B core antigen. Inside the core is the genome of HBV and DNA-dependant DNA-polymerase.
  • HBV genome: 3.2 Kbp molecule of circular dsDNA. The plus strand is incomplete leaving 15-50% of the molecule single stranded. The minus strand is complete and contains four overlapping open reading frames
  • P gene: codes for DNA polymerase. It has three distinct enzymatic activities
  • DNA polymerase
  • Reverse transcriptase
  • RNaseH
  • S gene: codes for protein which occurs in three forms
  • Large protein: translated from pre-S1, pre-S2 and S region; present in the infectious virion
  • Middle sized protein: translated from pre-S2 and S region
  • Small sized protein: translated from S region (most commonly found). Basic constituent of non-infectious HBsAg particles
  • C gene: Has two initiation sites that divide it into a pre-C &  C region producing two distinct proteins HBe Ag (secreted from the virus) and HbcAg (not secreted) respectively
iii. Morphological forms
  • Mature infectious virion/ Dane particle: 47nm diameter
  • Spherical particle: 22nm diameter, composed of HBsAg, non-infectious
  • Elongated tubules: 22nm diameter, length variable, composed of HBsAg, non-infectious
  • Antigenic structure
  • Group specific antigen ‘a’
  • Two type specific antigens: d or y/ w or r
  • Four antigenic types: adw, adr, ayw, ayr
iv. Commonest subtype in India: ayw; Western countries: adw
  • Cultivation
a) HBV has not been cultivated in the laboratory
  • Pathogenesis
a) Three main modes of transmission
b) Parenteral- Accidental inoculation of body fluids during medical, surgical, dental procedures, intravenous drug abusers, blood transfusion
c) Perinatal
  • Prenatal: transplacental
  • Perinatal: contamination of mucous membranes of the baby with maternal blood
  • Post natal: breast feeding
  • 90% of the babies infected at birth become chronic carriers as compared to 10% of those infected after the age of 6 years
c) Sexual
Clinical features
  • Prodromal (preicteric phase); I.P.: 6 weeks to 6 months. Malaise, anorexia, nausea, vomiting
  • Icteric phase: 2days to 2 weeks after prodromal phase. Jaundice, pale stools, dark urine
  • Convalescent phase: malaise and fatigue lasting for several weeks
Outcome of infection:
  • <1% of icteric cases develop fulminant hepatitis
  • 90-95% recover without sequelae
  • 5-10% develop chronic hepatitis which can lead to development of cirrhosis & hepatocellular carcinoma
Carriers: Persistence of HBsAg in the serum for more than six months
Chronic active hepatitis Chronic persitent hepatitis
Replicative phase Non-replicative phase
HbeAg+ HbeAg-
Anti-HbeAg- AntiHBeAg-
DNA exists in the free form in the hepatocyte DNA integrated into host genome
Intact virions presenting the circulation No intact virions present in the circulation
More infectious Less infectious
Serological markers of hepatitis b infection
HBsAg Anti-HBsAg HBeAg Anti-HbeAg Anti-HBcAg Interpretation
+ - + - - - Incubation period
+ - + - + - Acute hepatitis
+ - + - - + Chronic active hepatitis
+ - - + - + Chronic persistent hepatitis
- + - - - + Past infection
- + - - - - Vaccination
v. Laboratory diagnosis
  • Elevated AST, ALT
  • Raised serum bilirubin
  • Epidemiological marker of HBV infection: IgG-Anti-HbcAg
  • Surrogate marker of HBV replication: HbeAg
vi. Prophylaxis:
  • Passive immunization: HBIG
  • Active immunization:
  • Plasma derived hepatitis B vaccine
  • Recombinant yeast derived hepatitis B vaccine
  • Recombinant Chinese hamster ovary cell hepatitis vaccine
c. Hepatitis c virus
  • Belongs to family Flaviviridae
  • Placed in separate genus: Hepacivirus
  • 30-60nm, spherical, single stranded RNA, positive sense, positive sense, enveloped
  • Classified into 11 genotypes based on heterogeneity of nucleotide sequence.
i. Pathogenesis

Three main modes of transmission
  • Parenteral- Accidental inoculation of body fluids during medical, surgical, dental procedures, intravenous drug abusers, blood transfusion
  • Perinatal
    a. Prenatal: transplacental
    b. Perinatal: contamination of mucous membranes of the baby with maternal blood
    c. Post natal: breast feeding
  • Sexual
ii. Clinical features
  • Incubation period: 6-8weeks
  • About 75% infections sub-clinical
  • 50% patients develop chronic infection
  • Acute infection as compared to HBV infection is less severe, shorter duration of prodromal phase, milder symptoms. >85% cases of acute infection develop chronic disease
  • Fulminant infection: 0.1%
  • Patients with chronic disease may later on develop cirrhosis & hepatocellular carcinoma
Prophylaxis: no vaccine available currently
d. Hepatitis D virus
  • Defective virus requiring help from HBV (HBV necessary for the production of HDV virions)
  • Spherical, 36-38nm, HBsAg coat, HDAg nucleocapsid, single, circular RNA, minus strand
  • Genus: Delta virus
  • Parenteral/ Perinatal/ Sexual
  • Two types of infection:
  • Coinfection: simultaneous infection with HBV, HDV. Most commonly results from pareneral transmission. Infection more severe than HBV alone. IgM-Anti-HBcAg+
  • Super infection: Infection of HBV carrier with HDV. Commoner and more serious than coinfection (as liver function already compromised by HBV infection). Develops into fulminant infection. IgG-Anti-HBcAg+ 
i. Laboratory diagnosis
  • HDAg detection: ELISA
  • HDV RNA detection: PCR
  • IgM Anti-HDV detection: ELISA
ii. Prophylaxis
  • Prevention of infection with HBV
e. Hepatitis E virus- Belongs to family Caliciviridae
  • Spherical, 27-38nm, single stranded, positive sense RNA
i. Pathogenesis- Ingestion of contaminated drinking water
  • Virus first identified in New Delhi, India in 1955
ii. Clinical features
  • I.P.: 2-8 weeks
  • Disease resembles that produced by Hepatitis A virus
  • Fulminant infection: 1-2% in general population; 10-20% in pregnant women
  • Does not progress to chronic infection, cirrhosis or hepatocellular carcinoma
Laboratory diagnosis
  • Demonstration of virus particles: immunoelectron microscopy
  • Antigen detection: ELISA
  • Serology: IgM antibodies, ELISA
  • Nucleic acid detection: PCR

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