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 body's response to the virus.

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.

In real life 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. This outer shell is frequently referred to as the surface coat. The outer surface coat surrounds an inner protein shell, composed of HBc protein. This inner shell is referred to as the core particle or capsid. Finally the core particle surrounds the viral DNA and the enzyme DNA Polymerase.

How the virus reproduces

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.

First the virus attaches to a liver cells membrane.

The virus is then transported into the liver cell

The core particle then releases it's contents of DNA and DNA polymerase into the liver cell nucleus.

Once 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 from messenger RNA.

The cell then assembles 'live' copies of the virus. Via the above processes, versions of the Hepatitis B virus are constructed by the liver cell .

However because of the excess numbers of surface proteins produced many of these stick together to form small spheres and chains. These can give a characteristic "ground glass" appearance to blood samples seen under a microscope.

The copies of the virus and excess surface antigen 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 may result 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.

Hepatitis B Antigens

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.

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 performed using PCR which is expensive and difficult to perform and therefore not frequently used. Tests for HBV DNA are generally not performed as standard as other Hepatitis B markers such as the "e" antigen can be used to determine viral activity. It is generally only used research purposes, however in can be used to confirm the presence of Hepatitis B and or measure viral load for viral mutants that do not produce the "e" and/or normal surface antigens.

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.

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.

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(?).

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(?).

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(?).

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.

Antibodies to HBc (HBcAb, Anti-HBc).

The first detectable antibody to appear around 8 weeks after infection with HBV are antibodies to the HBV core protein. The initial antibodies are of class IgM and IgG and generally appear after the appearance of HBsAg but often before ALT elevations. These antibodies to HBcAg do not neutralise the virus. HBcAb's persist in serum after an infection with HBV and these are predominantly of type IgG. The presence of a strong IgM HBcAb's is indicative of acute phase infection. The presence of IgG HBcAb's with no IgM HBcAb's antibody may be present in chronic and resolved cases of Hepatitis B infection, this has been used to determine if the presence of HBsAb's was due to vaccination or by previous exposure to the live virus.

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 current theory is that the damage to liver cells is not caused directly by the virus, 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.

Interferon.

When a human cell is exposed to a new virus it usually produces a group of substances known as interferon's. It is believed that interferon's modulate (alter) the immune system, alter cell membranes to reduce infection of surrounding uninfected cells and also causes many other changes in the immune system. 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.

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 favorable prognosis.

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(?).

Acute Hepatitis B Infection

What happens when Initially infected.

First, HBV DNA and DNA polymeraise appear in the blood stream, several weeks later HBcAg and HBeAg is detectable . HBsAg is then appears in the blood stream and 1 to 6 weeks symptoms may appear, HBcAb is the first detectable antibody to appear. In the majority of cases as the immune system continues it's fight HBeAg disappears from the blood stream and a few weeks later HBeAb's appear. The level of ALT in the blood then starts to fall and HBsAg disappears from serum at about the same time as HBsAb's are first detected.

Symptoms.

An infected person may have zero, mild or severe symptoms that in some cases may prove fatal, in the elderly mortality rates can reach 10 to 15%.

When symptoms occur they normally begin with anorexia, malaise, nausea and vomiting and often fever. Diastase for cigarettes is common early sign. After around 3-10 days dark urine occurs and jaundice may follow. Other symptoms may include itching and pale stools. Symptoms then typically subside and the period of illness normally lasts between 4 to 8 weeks. Frequently an acute Hepatitis B infection is misdiagnosed as 'flu' and an infected person may not realise that they have been exposed to the virus.

Some cases may develop into fulminant, fatal liver failure.

Treatment

In most cases no special treatment is required for acute Hepatitis B infection and most people can safely return to work when jaundice (if any) resolves and once they feel well enough even though ALT has not returned to normal levels. However alcohol should be avoided until the infection has resolved itself.

Once HBsAb's appear the infection is considered to have been successfully defeated and the person is considered immune from future Hepatitis B infection.

Where symptoms are life threatening there is little that can be done although liver transplantation may be an option.

There is evidence to indicate that taking Milk Thistle can reduce the recovery period in cases of acute viral Hepatitis.

Prognosis

In the majority of cases prognosis is good and the individual will recover completely and be immune from subsequent Hepatitis B infection. However around 10% of cases do not clear up completely and a chronic infection remains.

Chronic Hepatitis B Infection.

How does chronic Hepatitis B Develop.

There are many factors that influence the probability of developing a chronic infection. Age is important and transmission from mother to infant at birth or infection while very young nearly always results in chronic infection (90%), In children the rate is lower (25%) and in healthy adults the risk of developing chronic infection is much reduced (2 - 5%). Other risk factors for developing chronic hepatitis include: being of the male gender; homosexual sexual orientation; having an altered immune system; there may also be genetic component with certain racial groups having a higher risk of chronicity but this has yet to be proved(?).

In up to 10% of people infected with Hepatitis B the HBsAg persists and HBsAb do not appear. If this persists for 6 months or more after acute infection then the condition is termed chronic. Of the 10% who develop chronic HB most are asymptotic carriers of the of the virus.

People with HBsAg, HBeAg, No HBsAb, No HBeAb are generally termed as having Chronic Active HB and around 50% of chronic cases are of the active form.

Symptoms

Most people with chronic persistent Hepatitis B are asymptotic carriers and do not develop liver severe liver problems and treatment with Interferon (IF) is not indicated.

Most people with chronic active Hepatitis B are also asymptotic carriers but are at increased risk of severe liver problems, very infectious and treatment with IF, currently the only treatment proven to be of benefit, (although others are being developed) is indicated.

Most people without symptoms are diagnosed following routine blood tests however around 33% of people with chronic Hepatitis B have some symptoms of infection. Vague symptoms including general malaise, tiredness, fatigue, weakness, exhaustion. loss of appetite, nausea, general abdominal discomfort or just feeling "unwell" are common. Sometimes symptoms include a low grade fever and jaundice is variable. Due to the unspecific nature of these symptoms diagnosis may take an extended period and even be misdiagnosed or attributed to psychological problems. Others develop diseases such as ulcerative colitis, pulmonary fibrosis, nephritis, acne and heamolytic anaemia. Other signs of liver disease sometimes present such as spider nevi, splenomegaly and retention of fluid. However only a minority of people are diagnosed after developing signs of cirrhosis.

Caution must be taken to avoid transmitting the virus and you should be checked by your doctor periodically to monitor liver function etc.

Most people with chronic active Hepatitis B are also asymptotic carriers but are at increased risk of severe liver problems, very infectious and treatment with interferon, currently the only treatment proven to be of benefit (although others are being developed) is indicated. Some people with chronic Hepatitis B have "flare ups" where they have the symptoms of acute hepatitis.

Treatment

At present theonly treatment generally available in conventional medicine is interferon although several new drugs and treatments are being researched. Interferon and experimental drugs are covered in their own chapter.

At present a liver biopsy is the only way to firmly establish the exact extent of a Hepatitis B infection and to assess any damage done to the liver. A biopsy is often required before starting and on completion of any treatment so the effectiveness of the treatment can be assessed.

Prognosis

If you remain infected with Hepatitis B then:-

• There is a chance the condition will clear up on it's own. (2-5% per year)
• There is an increased risk of liver cancer (5%)
• There is risk of liver cirrhosis (25%) or other severe liver problems. This is most likely if you have chronic active HB. This can be fatal or a liver transplant may be required.
• You may be highly infectious and can infect other people.