Hepatitis B Virus (HBV) Overview

The
Hepatitis B
Version 4.1

is now available.


Contents of this page :
1.0 What is Hepatitis
2.0 What is Hepatitis B
2.1 How is Hepatitis B Transmitted
2.2 What happens when infected with Hepatitis B
2.3 How Can I prevent infection
3. The hepatitis B virology and immunology
3.1 What is the Hepatitis B Virus.
3.2 How does the virus replicate.
3.3 Hepatitis B Antigens and Markers.
3.4 How the Human Body Responds to Infection.

1. What is Hepatitis

Hepatitis is an inflammation of the liver. It is usually caused by viral infections, toxic agents or drugs but may be an autoimmune response. It is characterised by jaundice, abdominal pain, liver enlargement and sometimes fever. It may be mild, or can be acute leading to fulminant hepatitis Others, usually viral or alcoholic are chronic, and can lead to cirrhosis and liver cancer.

The different types of VIRAL hepatitis are A (formerly called infectious hepatitis), B (serum hepatitis), C ( formerly called non-A, non-B hepatitis), D (delta hepatitis), E (a virus transmitted through the faeces of an infected person), F, G, cryptogenic (Caused by a virus as yet unidentified).

More hepatitis viruses are being discovered, but may be less common. Other viruses, such as Yellow Fever, Epstien Barr (EBV) and cytomegalovirus (CMV) as well as parasites and bacteria, can cause hepatitis as a secondary effect.

Many chemicals are damaging to the liver, as are drugs. The most famous drug which can do damage to the liver (if taken in excess) is acetaminophen (paracetamol).

Other types of hepatitis are: Autoimmune, Wilson's disease, hemochromatosis, and alcoholic hepatitis.

The various forms of viral hepatitis are caused by different and distinct viruses. Although within each virus there are various strains and mutant viruses. But as they are different treatment, symptoms and prognosis may vary, for further information on A, C, D, E, F and G please consult other sources.

2. What is Hepatitis B

Hepatitis B is caused by the hepatitis B virus, the virus is very common in Asia, China, Philippines, China, Africa and the Middle east. In Europe and North America the incidence of known carriers is about 1 in a 1000 people. It is estimated that there are 280 million carriers world-wide representing more than 5% of the global population.

2.1 How is Hepatitis B Transmitted

Hepatitis B (HB) is transmitted by the exchange of body fluids e.g. Blood, Semen, Breast Milk and in some circumstances saliva. People most at risk include: Anybody who has unprotected sexual intercourse; IV drug users who share needles and syringes; Health care workers in contact with potentially contaminated blood or body fluids; Babies born to mothers with the virus; Anyone in intimate contact with the infected person. Many cases of acute hepatitis B occur sporadically with no known source and studies have shown that prior unrecognised infection is common.

2.2 What happens when infected with Hepatitis B


Fig 1. Evolution in time of HBV infection.
Copyright image credit

It is possible to be infected with the hepatitis B virus (HBV) and experience no illness or symptoms whatsoever. Commonest is an acute attack of hepatitis during which you may feel unwell, tired and lose your appetite. Sometimes there is the characteristic yellowish colour of jaundice (Fig 1.) best seen in the whites of the eyes. This can last from a few days to a few months. Itching skin and pale stools may also occur. 90% of people infected with hepatitis B recover completely and become immune to the virus. Blood tests will show antibodies to hepatitis B indicating you have had hepatitis B but are now immune and cannot get hepatitis B again. However 10% of people infected with hepatitis B develop chronic infection, may have ongoing symptoms and they continue to be infectious for a variable length of time. Chronic infection is defined as having hepatitis B present for 6 months or more.

People with a chronic hepatitis infection are at risk of liver damage 20-30% of those will progress to cirrhosis.

2.3 How Can I prevent infection

 i) Vaccination
A safe and effective genetically engineered vaccine for hepatitis B is available. It is given in 3 subcutaneous injections (just under the skin) generally over a period of 6 months and conveys immunity in 90 to 95% of people treated. At the end of the course of injections a blood test is taken to see if you have developed the required antibodies. For the 5 - 10% of people who do not respond some new research has shown that a repeat course of injections given intramuscularly can create an immune response in between 62-98% (depending on several factors) of those who did not respond or whose response did not last when given subcutaneously.

Once vaccinated present it is important to be periodically tested to ensure that the body has sufficient levels of antibodies to prevent infection and a single booster dose may be required every 5 to 10 years to ensure immunity from infection.

At present vaccines are ineffective for those already infected with the hepatitis B virus.

New vaccines are being developed and some of these promise increased response rates, only require a single injection and some may be effective for people with chronic hepatitis B. However these are still in the research stage and not generally available.

 ii) After exposure to the virus
If an unvaccinated individual is exposed to the virus accidentally, hepatitis B Immune globulin can be given. Ideally within 24 hours of exposure and no later than 7 days after exposure, a repeat dose is necessary 28 - 30 days later. Hepatitis B Immune globulin is generally given where there is a known risk of infection, e.g. via needle stick injury or to new-born infants born to HBsAg positive mothers. In many cases hepatitis B Immune globulin can prevent initial infection with hepatitis B but there are also a significant number of cases where it has not prevented infection after exposure.

3. The hepatitis B virology and immunology

In order to understand what happens when a person is infected with hepatitis B it is helpful to know more about the virus. This section attempts to convey information about the hepatitis B virus, how it reproduces and the human bodies response to the virus. This one chapter could fill a text book, or more, and so the information is simplified.

3.1 What is the Hepatitis B Virus.

Hepatitis B is a DNA Virus of the hepadnaviridae family of viruses. It replicates within infected liver cells (hepatocytes ). The infectious ("Dane") particle consists of an inner core plus an outer surface coat.

To aid visualisation a conceptual and a real pictures are shown below:

ssssssss

s

s

s

cccc

s

s = surface proteins

s

cpDpc

s

c = core protein

s

cpDpc

s

D = Viral DNA

s

cpDpc

s

p = DNA Polymerase

s

cccc

s

s

s

Fig 2. - Conceptual view of the Hepatitis B Virus.

ssssssss

Fig 3. - Hepatitis B Virus (HBV).
Copyright A.J.Cann

In real life (Fig 3.) the virus is a spherical particle with a diameter of 42nm (1nm = 0.000000001 metres) and is composed as follows. There is an outer shell (or envelope) composed of several proteins known collectively as HBs or surface proteins (indicated by 's' in Fig 2.). This outer shell is frequently referred to as the surface coat. The outer surface coat surrounds an inner protein shell, composed of HBc protein (shown as 'c' in Fig 2). This inner shell is referred to as the core particle or capsid. Finally the core particle surrounds the viral DNA ('D') and an enzyme DNA Polymerase ('p').

3.2 How does the virus replicate.

When the virus enters the body of a new host it's initial response, if it's gets past the immune system, is to infect a liver cell. To do this the virus attaches to a liver cells membrane and the core particle enters the liver cell. The core particle then releases it's contents of DNA and DNA polymerase into the liver cell nucleus.

From within the cell nucleus the hepatitis B DNA causes the liver cell to produce, via messenger RNA; surface (HBs) proteins, the core (HBc) protein, DNA polymerase, the HBe protein, HBx protein and possibly other as yet undetected proteins and enzymes.

DNA polymerase causes the liver cell to make copies of hepatitis B DNA. I.e. it is believed that the replication of HBV DNA it does not go via RNA(?). Via the above process, versions of the hepatitis B virus are constructed by the liver cell . These copies of the virus and are released from the liver cell membrane into the blood stream and from there can infect other liver cells and thus replicate effectively. However when reproducing, mistakes may be made in copying viral DNA and this results in different strains and mutant strains of hepatitis B occurring.

The incubation of the Hepatitis B Virus (hepatitis B) is about 6 to 25 weeks (i.e. before physical and generally detectable histological or physical symptoms occur) however there are several biochemical and histological changes that occur in stages after infection with the hepatitis B virus.

3.3 Hepatitis B Antigens and Markers.

The various components produced by hepatitis B, while reproducing, are detailed below. Some of these components enter the blood stream and cause detectable changes, some may only be determined via liver biopsy and others require sophisticated, experimental or unreliable tests.

i) Hepatitis B DNA (HBV DNA)
This is one of the first things that can be detected in the bloodstream after initial infection. It can be detected as soon as 1 week after infection using sensitive tests. It is believed that the level of HBV DNA may indicate how fast the virus is replicating(?). The test for HBV DNA is however expensive and difficult to perform, it is therefore not frequently used. Tests for HBV DNA are not performed as a standard test and generally only used as indicators of disease progression, suitability for therapy and research purposes.

ii) Hepatitis B DNA polymerase. (HBV DNA Polymerase, DNAp)
This enzyme can be detected in the bloodstream soon after initial infection by hepatitis B at about the same time as HBV DNA. I.e. generally within a 1 week or so after infection. Tests for HBV DNA polymerase are not performed as a standard test and generally only used as indicators of disease progression, suitability for therapy and research purposes.

iii) Hepatitis B Core protein. (HBcAg)
The core protein (HBc) is not detectable in the bloodstream, however it can be detected in the sample of liver cells taken after a liver biopsy. Generally the HBc proteins link together to form the hepatitis B core that encapsulate HBV DNA and DNA Polymerase.

iv) Hepatitis B Surface protein(s). (HBsAg)
The outer surface coat composed of hepatitis B surface proteins is produced in larger quantities than required for the virus to reproduce. The excess surface proteins clump together into spherical particles of between 17-25nm in diameter but also form rods of variable length. In some cases these particles encapsulate a core particle and produce a complete, and infectious, virus particle that enters the blood stream and can infect other liver cells. The excess spheres, rods and also complete viral particles enter the blood stream in large numbers and are easily detectable. It does however take a while for these proteins to appear.

The incubation of the Hepatitis B Virus (hepatitis B) is between 6 to 25 weeks. After infection and 1 to 6 weeks before symptoms occur HBsAg appears. A positive test for the presence of hepatitis B surface protein (HBsAg), is the standard currently taken to indicate current infection with hepatitis B. If HBsAg is present for more than 6 months this is generally taken to indicate chronic infection.

It is thought that excess HBs proteins produced may allow infectious viral particles to escape the immune system by mopping up any low levels of surface antibodies that may be produced by the immune system(?).

v) HBe Protein. (HBeAg or 'e' antigen)
The Hepatitis 'e' antigen (HBeAg) is a peptide and normally detectable in the bloodstream when the hepatitis B virus is actively reproducing, this in turn leads to the person being much more infectious and at a greater risk of progression to liver disease. The exact function of this non structural protein is unknown, however it is thought that HBe may be influential in suppressing the immune systems response to HBV infection(?). HBeAg is generally detectable at the same time as HBsAg and disappears before HBsAg disappears. The presence of HBeAg in chronic infection is generally taken to indicate that HBV is actively reproducing and there is a higher probability of liver damage. In acute infection HBeAg is generally only transiently present.

However mutant strains of HBV exist that replicate without producing HBeAg. In many cases infection with these mutant strains is more aggressive than HBe producing strains(?).

vi) HBx Protein.
The function of this protein is not yet known. Although it can be detected current tests are unreliable as other proteins interfere with the results(?).

3.4 How the Human Body Responds to Infection.
This section details how the human body responds to an initial infection with hepatitis B. In people with immune suppression, undeveloped immune systems (I.e. infants and children), certain genetic traits or other as yet unknown factors these may not occur.

Round 90% of infected people will recover from Hepatitis B and around half of these will have had no symptoms. Recovery means that no HBsAg is found in the blood and the Hepatitis B Antibody (HBsAb) is present. HBsAb usually persists for life after recovery.

i) Antibodies to HBc (HBcAb).
The first detectable antibody to appear around 8 weeks after infection with HBV are antibodies to the HBV core protein. These antibodies to HBcAg (HBcAb) do not neutralise the virus. HBcAb's persist in serum after an infection with HBV has been defeated and testing for this antibody has been used to detect previous exposure to the live virus.

ii) ALT alanine aminotransferase and AST (aspartate aminotransferase).
ALT and AST are enzymes produced in liver cells that can be detected in the blood stream. The normal range for ALT is between 0-40. When liver cells are damaged these enzymes are released and elevated levels are detected in serum. The value of ALT in the blood stream is generally taken to be an indicator of the damage that hepatitis causing to liver cells. However damage may be occurring with little or no elevation of ALT (this is especially true for hepatitis C and people with end stage liver disease).

ALT and AST and other substances are measured when a liver function test is taken. However other drugs and especially alcohol can elevate these readings artificially. It is therefore important to avoid these things before a liver function test and/or inform your doctor of any drugs you may be taking or have taken in weeks previous to the test. You may find it useful to keep a record of your ALT to track disease progression and the effects any treatments) you are taking is having.

After an initial infection and at around the same time as HBcAb appears in the blood stream the level of ALT starts to rise sharply. The rise in ALT is due to damage to the liver cells, one theory is that the damage to liver cells is not caused directly by the virus, i.e. the virus does not kill liver cells, but by the human bodies own immune system killing infected and surrounding cells. In patients with compromised immune systems and/or with HIV infection there is increased risk of the infection becoming chronic but damage done by the chronic infection appears mild in comparison to people not infected with HIV. In cases of acute infection ALT starts to drop at around the same time as when the 'e' antigen is no longer detectable and is down to normal when antibodies to the surface antigen appear.

iii) Interferon.
When a human cell is exposed to a new virus it usually produces a group of substances known as interferons. It is believed that interferons modulate (alter) the immune system, alter cell membranes to reduce infection of surrounding uninfected cells and also causes many changes. This naturally produced interferon assists the body in fighting hepatitis B. However it was discovered that the interferon response was deficient in some people and also infants/ children with immature immune systems. This finding lead to interferon being considered as a treatment.

iv) Antibodies to HBe protein (HBeAb)
Antibodies to the 'e' antigen (HBeAb) normally appears a few weeks after HBeAg is no longer detectable. The presence of HBeAb is generally taken to be a good sign and indicates a favourable prognosis.

v) Antibodies to HBs protein (HBsAb)
These are generally the last antibodies to appear. HBsAb can neutralise the hepatitis B virus and there appearance taken as an indicator that an initial infection has been defeated.

HBsAb can also be induced to appear by vaccination and so provide protection against hepatitis B. However the immune response produced by vaccination may not be 100%. Although very rare, hepatitis B infection has occurred in vaccinated individuals. It is believed that this may be due to mutant virus strains that express different surface proteins to those used in the genetically engineered vaccine(?).

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GLOSSARY

Next chapters :

4. Acute Hepatitis B Infection,
4.1 What happens when Initially infected.
4.2 Symptoms.
4.3 Treatment
4.4 Prognosis
5. Chronic Hepatitis B infection.
5.1 How does chronic Hepatitis B Develop.
5.2 Symptoms
5.3 Treatment
5.4 Prognosis
6. Liver Biopsy
6.1 What is a Liver Biopsy?
6.2 What are the different ways Liver Biopsy can be performed?
6.3 When is a Liver Biopsy used?
6.4 What are the dangers of Liver Biopsy?,
6.5 Are there alternatives to Liver Biopsy?,
6.6 Do Liver Biopsies ever need to be repeated?,
6.7 Biopsy results.,
6.8 Grading of liver biopsies.,
6.9 What do I need to do if I'm having a biopsy.

 

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