1. HEPATITIS VIRUSES
Part 2

2. Pathogenesis of HBV Infections
HBV is transmitted only in blood and body fluids
Replication starts in the hepatocytes, “the only host cells”
HBsAg particles are liberated into blood stream, “they are not infective”
Dane particles “complete virion” are so numerous, up to 1010/ml, ml of blood can transmit infection
Incubation period days
Liver injury may be due to cellular immune response directed toward the new antigens deposited in the cell membrane of infected cells

3. Pathogenesis of HBV Infections
Acute Infection
Follows initial infection and is characterized by a high rate of viral replication.
Damage to liver cells which results in:
high blood concentration of liver enzymes
and the obstruction of small bile tubes due to inflammation leads to the development of jaundice.
In severe cases liver function may be so damaged that clotting is impaired or hepatic encephalopathy develops. This is referred to as acute fulminant hepatitis.

4. Pathogenesis of HBV Infections
Percentage of acute infection that will not be cleared and become chronic infection:
Between 1% and 4% of adults,
about 70–80% of infants and children,
and 90% of neonates
40% of hemodialysis patients
and up to 20% of patients with immune deficiencies.

5. Pathogenesis of HBV Infections
Chronic infections
Chronic HBV infection is defined as HBV infection lasting longer than 6 months.
It includes a spectrum from chronic asymptomatic carrier state to chronic active hepatitis with rapid progression to cirrhosis.
Chronic persistent (carriers):
are often asymptomatic and may not be aware that they are infected;
they are capable of infecting others
no anti HBsAg “antibodies”
“mild degree of liver damage”

6. Pathogenesis of HBV Infections
Chronic active hepatitis:
develops in more than 25% of carriers and often results in cirrhosis
Significant damage to the liver
Patients at risk may develop cirrhosis or hepatocellular carcinoma which arises as a result of integration of viral genome into the DNA of the hepatocytes.

7. Laboratory Diagnosis
HBV infection cannot be differentiated on the basis of clinical symptoms alone, and definitive diagnosis depends on the results of serologic testing
Serologic markers of HBV infection vary depending on whether the infection is acute or chronic.
Liver function tests, abnormally elevated “transaminases, bilirubin, alkaline phosphatase, LDH”
The presence of HBsAg confirms diagnosis, tested by ELISA, PCR, RIA
Liver biopsy

8. Laboratory Diagnosis
HBsAg is the most commonly used test for diagnosing acute HBV infections or detecting carriers.
HBsAg can be detected as early as 1 or 2 weeks and as late as 11 or 12 weeks after exposure to HBV when sensitive assays are used.
The presence of HBsAg indicates that a person is infectious, regardless of whether the infection is acute or chronic.

10. Laboratory Diagnosis May be recovering from acute HBV infection
May be distantly immune and the test is not sensitive enough to detect a very low level of anti-HBs in serum
May be susceptible with a false positive anti-HBc
May be chronically infected and have an undetectable level of HBsAg present in the serum

11. Control of HBV Infections
Blocking of person-to-person transmission, prevent blood or body fluids of infected persons gaining access to the circulation of someone else.
Active immunization with HBsAg obtained by recombinant DNA technology (in yeast) for high-risk groups and infants or plasma derived vaccine.
Passive immunization: Human immunoglobulin with a high titer of anti-HBs (HBIg: hepatitis B immunoglobulin), which gives immediate passive protection, should be given with active vaccine.
HBIg is given for healthcare staff who suffer “needle-stick”.

12. Treatment
Two major groups of antiviral treatment have been licensed for the treatment of chronic HBV infection in many countries.
These include interferon alpha (IFNa, or PEG-IFNa) and nucleoside or nucleotide analogues such as lamivudine.
 Polyethylene glycol (PEG) is added to make interferon last longer in the body.

13. Hepatitis C It belongs to Flaviviridae family genus hepacivirus
HCV diameter is 50 nm
Icosahedral symmetry, Enveloped
Positive single stranded RNA
There are 6 major genotypes (1-6)
HCV has 2 envelope glycoproteins; E1 and E2,
two transmembrane proteins; NS1 and NS2 in addition to RNA polymerase (NS5B) and interferon resistance protein(NS5A)
HCV has a high mutation rate
HCV has high rate of replication, one trillion particles per day
Transmission is similar to HBV

14. Epidemiology Incubation period: 2-26 weeks
An estimated 170 million people are infected world-wide with HCV.
About 2-3 million people are infected per year
Co-infection with HIV is common
HCV is considered to be the most common cause of post- transfusion hepatitis.

16. Pathogenesis Acute hepatitis C
It refers to the first 6 months after infection with HCV.
Between 60-70% of infected people develop no symptoms during the acute phase.
Symptoms include decreased appetite, fatigue, abdominal pain, jaundice and itching.
HCV is detected in blood within 1-3 weeks after infection using PCR technique.
Antibodies are detectable within 3-15 weeks.
Viral clearance rates are highly variable, 10-60% of infected persons clear the virus during the acute phase as shown by normal liver enzymes.
Most patients develop chronic infection lasting more than 6 months

17. Pathogenesis Chronic hepatitis C It is often asymptomatic.
One third of patients progress to liver cirrhosis in less than 20 years, others may develop liver cancer.

18. Treatment IFN-α-2a injection
Ribavirin tablets (a purine nucleoside analogue), it inhibits viral RNA polymerase, it may cause shift of TH2 into TH1.
Treatment may last for weeks depending on HCV genotype.
Vaccination against HAV and HBV is strongly recommended, as infection with a second virus could worsen their liver disease.
No vaccine against HCV is available.
Alcoholic beverages consumption accelerates HCV associated cirrhosis and makes liver cancer more likely.
Smoking may have the same effect.
Amantadine may be effective in combination with IFN-α and Ribavirin.
HCV resistant strains develop against IFN-α and/or Ribavirin
Th1 helper cells are the host immunity effectors against intracellular bacteria and protozoa while Th2 against extracellular parasites
Helper T cells are arguably the most important cells in adaptive immunity, as they are required for almost all adaptive immune responses. They not only help activate B cells to secrete antibodies and macrophages to destroy ingested microbes, but they also help activate cytotoxic T cells to kill infected target cells.

19. Laboratory Diagnosis Liver enzymes increased (ALT in particular) PCR
Used to diagnose HCV in the acute phase
To monitor the response to antiviral therapy
Anti HCV antibodies
Genotyping is recommended to determine the length and potential response to IFN-α.

20. Delta Agent (HDV) Incomplete RNA virus HBV-dependent “for replication”
It may be transmitted along with HBV
May be detected in hepatocyte nuclei of patients with chronic HBV infection
Its outer coat is formed from HBsAg
It uses HBV S antigen to provide the protein for its envelope and thus HDV can only replicate and spread within HBV-infected individuals.
Recovery is usually complete and development of chronic hepatitis D is rare (less than 5% of acute hepatitis).

21. Laboratory Diagnosis
Diagnosis of the active infection depends on detecting the delta antigen or its IgM antibody in the blood
Immunization against HBV also protects against infection with delta agent

22. Hepatitis E Virus “HEV”
RNA(+), single stranded.
Icosahedral symmetry, nonenveloped.
Size: nm.
HEV has one serotype and 4 genotypes.
Genotypes 1 and 2 are restricted to humans.
Genotypes 3 and 4 infect humans, pigs and other animal species.
In addition an avian virus has been described which causes hepatitis-spleenomegaly syndrome in chickens.
Spread via fecal-oral route
Clinically, it is comparable to HAV.
HEV causes severe infection in pregnant women.
Incubation-period 2-7 weeks
A vaccine has been developed recently which is based on recombinant viral proteins, (registered in China).

23. Laboratory Diagnosis
Definitive diagnosis of hepatitis E infection is usually based on the detection of specific IgM antibodies to the virus in a person’s blood; this is usually adequate in areas where disease is common.
Additional tests include reverse transcriptase polymerase chain reaction (RT-PCR) to detect the hepatitis E virus RNA in blood and/or stool.
This test is particularly needed in areas where hepatitis E is infrequent, and in cases with chronic HEV infection.