Ow, my liver! (or, Why hepatitis is a real pain in the stomach)

Hepatitis, which has the defining feature of liver inflammation, can be due to a variety of reasons, including consuming excessive amounts of alcohol and/or other toxins, bacteria, and viruses. One of the most important viruses in hepatitis is the hepatitis B virus (HBV). Image

Hepatitis B is endemic in many parts of the world, including sub-Saharan Africa, East Asia, and eastern and central Europe. Transmitted by body fluids and blood, HBV causes liver inflammation, vomiting, fatigue, fever, and jaundice; in less than 1% of cases, HBV causes fulminant hepatitis, which has a high mortality rate. Approximately 5%, or 350 million, are chronic carriers who go on to develop cirrhosis of the liver, and liver cancer. In endemic areas, transmission of HBV most frequently occurs from mother to her unborn child; this is known as vertical transmission. In non-endemic areas, HBV is transmitted from person to person most frequently by unprotected sex or needle sharing; this is known as horizontal transmission. The infection early on in life occurring from vertical transmission is correlated with a higher chance of chronic infection, possibly because the baby’s immune system gets used to the HBV antigen, and does not recognize it as a foreign protein; thus the immune system is unable to clear the virus from the body.

Hepatitis B virus schematic

Schematic of HBV; HbsAg is Hepatitis B surface antigen; HbcAg is Hepatitis B core antigen; notice the partially double-stranded DNA genome.

HBV is a hepadnavirus, with a partial double-stranded DNA genome and a viral envelope. It is also one of the smallest animal viruses, measuring just 42nm across. To infect us, the HBV binds to the surface of a hepatocyte (liver cell), and enters the cell. It then moves to the cell nucleus, and delivers the partial double-stranded genome into the nucleus. In the nucleus, the genome is completed so as to become fully double-stranded, and thus the complete genome can now serve as the template for the four viral RNAs that will eventually produce more copies of HBV viral particles and its genome. After more copies have been produced, the various parts that make up a HBV virion self-assemble, forming many more virions, and exit the cell to infect more hepatocytes.

HBV is unusual; it is a pararetrovirus – that is to say, it is one of the few known non-retroviruses that use reverse transcription in its replication. Reverse transcription is noteworthy because it reverses the usual flow of information from DNA to RNA, and instead goes from RNA to DNA. However, HBV is not a retrovirus because it has an RNA intermediate instead of a DNA intermediate, meaning that the genetic information flow in HBV replication goes from DNA à RNA à DNA, instead of RNA à DNA à RNA, as in retroviruses.

In the process of replication, HBV produces a large amount of excess viral particles, so much so that one of the first instances that viral particles were detected was from the blood serum of HBV infected people; they are non-infectious because they do not have a genome. These genome-less viral particles are known as virus-like particles (VLPs), and have become important in vaccine creation because of they are very immunogenic, while at the same time being non-infectious. HBV VLPs are commonly spherical or filamentous, compared to the spherical HBV virion.

HBV has four serotypes, and eight genotypes. Different serotypes produce different antibody reactions from our adaptive immune system; however, the genotype of a HBV virion has no relation with which serotype is presented on its surface. Genotypes are correlated with the geographical distribution of HBV, with some genotypes being more predominant in some regions; we are also able to trace the evolution of HBV through its genotypes.

Although HBV does cause cell damage upon infection, a lot of damage is done by the reaction of our immune system to infection. After being activated by antiviral cytokines, white blood cells, particularly virus-specific cytotoxic T cells, set about destroying infected hepatocytes, thus causing liver inflammation, and other liver-related symptoms, such as jaundice and liver cancer. When T cells die as a result of responding to the infection, more antiviral cytokines are produced. The higher the level of antiviral cytokines, the stronger the signal to recruit more T cells, resulting in more hepatocytes destroyed, and more severe liver inflammation.

Treatment primarily deals with interfering with DNA synthesis via nucleoside and nucleotide analogues, thus interrupting HBV replication. Unfortunately, there is no drug available that will help infected persons clear HBV from their bodies faster.

The first vaccines were essentially injections of HBsAg (HBV surface antigen) that would induce the production of antibodies to counteract HBsAg, and consequently HBV virions themselves. They were initially purified from the blood of people already infected with HBV; all viruses were destroyed, leaving behind the HBsAg. This was withdrawn over fears of HIV contamination, as the people most likely to have HBV were also at high risk for HIV. Recombinant vaccines were then developed, where the gene for HBsAg was transfected into yeast, thus producing HBsAg without the risk of contamination from other pathogens. Because HBsAg is able to self-assemble into VLPs, these vaccines are also considered the first VLP vaccines. This is also one of the first vaccines against cancer, due to the link between chronic HBV carriers and liver cancer.


WHO | Media Center | Hepatitis B

WHO | Global Alert and Response | Hepatitis B

D. Grimm, R. Thimme, and H. E. Blum. HBV life cycle and novel drug targets Hepatol Int. 2011 June; 5(2): 644–653. doi:  10.1007/s12072-011-9261-3

A. J. Cann. Principles of Molecular Virology, 4th Edition. Elsevier 2005


Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s