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Members of the Hepadnaviridae Family | Clinical Manifestations | Epidemiology | High Risk Populations | Transmission | Tropism | Cancer Members of the Hepadnaviridae Family: HEPADNAVIRIDAE family lineage
WHV and GSHV both are morphologically the same as HBV and have about 60% of the same sequence as HBV. HBV only grows in humans and chimps, but not baboons or lower animal species. Clinical Manifestations: How do you know you have Hepatitis B? 30% of infected individuals do NOT have symptoms. Those who do present with jaundice, fatigue, abdominal pain, loss of appetite, nausea, vomitting, and joint pain. Fever can be absent or mild. After infection, the incubation period between exposure and first symptoms is 45-120 days, averaging around 60-90 days. This period is affected by the amount of virus in the inoculum, mode of transmission, and factors relating to the host. Primary infection is usually associated with little or no liver disease and mild to fulminant hepatitis. The next phase of disease, icteric phase, usually occurs 10 days after symptoms begin. Dark urine followed by pale stools, yellowish coloring in the mucous membranes, conjunctivae, sclerae (whites of eyes), and skin then appear. Clinically, Jaundice is indicated by bilirubin levels of 20-40mg/L. It is accompanied by hepatomegaly and splenomegaly. The infection usually resolves after 4-8 weeks. Most patients recover with few consequences and without recurrence in the future. Young children rarely are affected and develop disease; however those that are are at a high risk of becoming chronic carriers, especially if they are under the age of 7. The hallmark of acute Hep B infection is a large increase in serum transaminase (aminotransferase) activity.
Epidemiology: Where is Hepatitis B found? There are 350 million carriers of Hepatitis B worldwide and most of them are concentrated in developing countries. Hepatitis B is a disease of the poor. Sub-Saharan Africa, most of Asia, and the Pacific are hit hardest. The Amazon, southern parts of Eastern Europe, and Central Europe are also affected. In Western Europe and the United States, the prevalence is only 1%. It is estimated that there are 1.2 million carriers in the United States. Most of these individuals are infected during childhood and up to 10% of them become chronically infected. In these regions, liver cancer is one of the top 3 killers of adult males.
*Courtesy of CDC.gov: http://www.cdc.gov/mmwr/PDF/rr/rr5416.pdf High-Risk Populations: Who gets Hepatitis B? According to the WHO, the populations below are at high-risk of becoming infected with HBV.
Keep in mind that 1/3 of patients with hepatitis do not fit in any of these categories. The source of the infection cannot be identified in 35% of HBV cases. Transmission: How do people get Hepatitis B? Hepatitis B is transmitted parenterally (through bodily fluids) during blood contamination, sexual contact, breast feeding, or perinatal exposure. Contact with infected blood does not have to be extensive in order for the virus to be transmitted. Levels of virus in the serum of an infected individual can reach very high levels. Therefore, medical personnel are at risk of contracting the virus from their patients from needle sticks and contact with contaminated blood. Infants born to HBeAg-positive mothers (those who have high levels of viral replication) have a 70-90% chance of being born infected. Hepatitis B is 100 times more infectious than HIV. The Hepa in Hepadnaviridae stands for hepatotropic which means they infect liver cells. All Hepanaviruses cause hepatitis in their respective hosts. Much of what is known about this family is from studying the infected liver in animal models or in primary hepatocytes. Their host ranges are narrow, which may be because of the types of receptors Hepadnaviruses use for entry into host cells. Transcription has been found to be most efficient in hepatocytes. In order to replicate optimally, some promoters require hepatocellular transcription factors (i.e. hepatocyte nuclear factor 1) which are primarily in hepatocytes. Two enhancer regions are known to function best in hepatocytes. One of the gene products, the X gene product, has also been found to upregulate transcription of viral DNA. Cancer: Hepatocellular Carcinoma 5 years after the discovery of Hepatitis B, Sherlock et al. discovered a link between HB and HCC in 1970. Liver cancer causes 500,000 deaths a year across the globe, and about 90% of those are HCC. 50-80% of all HCC patients are infected with HBV. Inversely, the risk of HCC to a chronic HBV patient is 10-25%. HCC is found more commonly in men than women (4:1) and is one of the top 10 cancers in humans. In endemic regions such as China, Taiwan, Southeast Asia, and sub-Saharan Africa, HCC is one of the 2 or 3 most common cancers. As one would predict, HCC is found more commonly in areas of high chronicity for HBV, usually affecting 5-10% in these populations. The pathogenesis of HCC is not exactly known, however one hypothesis is that long-term infection may lead to selection of tumor cells. About 90% of patients with HCC have cirrhosis - a condition where liver tissue is replaced by scar tissue - implying that HCC has to do with severe liver damage. HCC may also be a result of other causes of liver disease such as those associated with drinking alcohol or chronic Hepatitis C virus. Furthermore, HCC is associated with long periods of liver damage and regeneration, as HCC only appears 30-40 years after chronic HBV infection. Therefore, babies infected through perinatal transmission are at high risk of developing HCC. In woodchucks, WHV - one of the closest related viruses in the Hepadnavirus family to Human Hepatitis B virus - 40% of HCC cases in woodchucks occur at the site of WHV DNA integration near the N-myc2 gene. Almost every animal infected with WHV dies within 2-3 years of liver cancer. In humans, 85% of HCCs have integrated HBV DNA in the cells. Every cell in the tumor has the same HBV insertion and sequence, indicating that the DNA insertion occurred before cellular proliferation. Integration into the host genome is not a necessary step for the replication of the virus, therefore this integration is probably carried out by host mechanisms. This is not well understood. Evidence that the X protein might be responsible does exist, at least in part. The HBV X gene codes for a protein which binds to p53, an anti-oncogene. An important discovery was uncoverd when transgenic mice expressing the X gene developed HCC. However, this depended on the mouse strain. There is definitely more research to be done to understand the HBV X protein association because Hepatitis C viruses also cause HCC but lack the X gene.
* Images courtesy of http://virology.wisc.edu/virusworld/ICTV8/hpb-hepatitis-b-ictv8.jpg and www.research.amnh.org/exhibitions/ epidemic/hepb.html and http://www.who.int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf
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Orthohepadnavirus (mammals) genus
DHBV - Duck Hepatitis Virus (Ducks and Geese) 
