A Novel Hepadnavirus is Associated with Chronic Hepatitis and Hepatocellular Carcinoma in Cats.

In 2015, over 850,000 people died from chronic hepatitis and hepatocellular carcinoma (HCC) caused by hepatitis B virus (HBV). A novel hepatitis B-like virus has recently been identified in domestic cats. The pathogenic potential of domestic cat hepadnavirus (DCH), for which 6.5% to 10.8% of pet cats are viremic, is unknown. We evaluated stored formalin-fixed, paraffin-embedded biopsies of diseased and normal feline liver for the presence of DCH using PCR and in situ hybridization (ISH). DCH was detected in 43% (6/14) of chronic hepatitis cases and 28% (8/29) of HCCs, whereas cholangitis (n = 6), biliary carcinoma (n = 18) and normal liver (n = 15) all tested negative for DCH. Furthermore, in DCH-associated cases, the histologic features of inflammation and neoplasia, and the viral distribution on ISH were strikingly similar to those seen with HBV-associated disease. Several histological features common in human HBV-associated hepatitis, including piecemeal necrosis and apoptotic bodies, were identified in DCH-positive cases of chronic hepatitis. In two cases of HCC examined, the proliferation index in regions that were ISH-positive was higher than in ISH-negative regions. The intracellular distribution of virus in both hepatitis and HCC demonstrated that viral nucleic acid is present in both nuclear and cytoplasmic forms. Collectively, these findings demonstrate a compelling association between DCH and some cases of chronic hepatitis and hepatocellular carcinoma in the cat that mirrors features of HBV-associated hepatopathies. Future investigations of viral epidemiology and natural history are needed to establish the impact of DCH on feline health.

Long-term high-dose interferon-alpha therapy delays Hepadnavirus-related hepatocarcinogenesis in X/myc transgenic mice.

The role of interferon-alpha (IFN-alpha) remains unclear in prevention of virus-induced hepatocellular carcinoma in humans. We have investigated it herewith in the X/myc transgenic mouse model of Hepadnavirus-related hepatocarcinogenesis because of upregulation of c-myc oncogene in the liver. We have demonstrated that IFN-alpha can downregulate dose-dependently hepatocyte proliferation and c-myc overexpression at early premalignant stages, while it does not affect either hepatocyte apoptosis or telomerase activity at these steps. However, continuous and long-term administration of IFN-alpha dose-dependently delays tumor onset in dysplastic livers and increases overall survival of animals, more efficiently whether started before the onset of dysplasia. The present study therefore highlights that early preventive administration of IFN-alpha can slow down evolution towards hepatocellular carcinoma via repression of c-myc and hepatocyte proliferation at premalignant steps in experimental c-myc-induced hepatocarcinogenesis. However, the transient effect observed in this study emphasizes a need to clarify the possible mechanisms of acquired resistance and subsequent therapeutic escape. Our experimental model may be a pertinent tool to explore antioncogenic properties of IFN-alpha in human cirrhotic livers showing c-myc upregulation.

DHBV manipulation and prediction of the outcome of infection.

BACKGROUND/AIMS: The immunological response of ducks to acute infection with duck hepatitis B virus (DHBV) has not been fully characterised. In this study the relationship between viral dose and the outcome of infection in immune competent 26-day-old ducks was examined. METHODS: Indirect ELISA assays were developed to detect the presence of antibody to DHB surface antigen and DHB core antigen. A DHBV serum pool was titrated in 1-day-old and 26-day-old ducklings. RESULTS: The ID50 dose of the ducks injected at 26 days of age was found to be 1000 times that of the ducks injected on day of hatch. The antibody responses and serum DHBV DNA were followed in eight ducks inoculated with DHBV positive serum when 26 days of gene and in three ducks infected with DHBV on day of hatch. The three ducks infected on day of hatch were viraemic by day 7 and remained highly viraemic throughout the experimental period. In the older ducks, inoculation with 1000ID50 resulted in the development of chronic carriage, while inoculation with either 100 or 10ID50 doses resulted in acute infection with or without viraemia. These ducks were able to clear the infection from their circulation, but only 50% cleared DHBV from the liver within the experimental period. All infected ducks developed anti-core activity. Only non-viraemic ducks developed anti-surface activity. CONCLUSION: DHBV infection can be established in immune competent adolescent ducks, with variable disease outcomes comparable to HBV infection in humans.

Duck hepatitis B virus (DHBV) infection in Indian domestic ducks: a pilot study.

One hundred and two apparently healthy Indian domestic ducks from the Poultry Research Station, Madras were screened for duck hepatitis B virus (DHBV) infection by; 1. screening for the duck hepatitis B virus surface antigen (DHBsAg) in their sera using hepatitis B virus (HBV) reagents, 2. screening for DHBsAg using specific duck hepatitis B virus (DHBV) reagents and 3. demonstration of DHBV DNA using DHBV DNA probe by dot blot hybridisation. While 5 ducks (4.9%) were consistently positive with HBV reagents, use of DHBV reagents showed a total of 4 ducks (including 3 of the above 5) to be positive for DHBsAg. DNA hybridisation showed 6 ducks to be positive for DHBV DNA. On clinical examination, 5 out of these 6 ducks did not reveal abnormalities, the other one showed hepatomegaly and ascites. Post-mortem studies showed the presence of nodules on the surface of the liver in all 5 which were positive with HBV reagents including the one with hepatomegaly. On histopathological evaluation, they were found to be hepatocellular carcinoma with or without bile duct carcinoma. The present study is a pilot report on the occurrence of DHBV infection in Indian domestic ducks and the possibility of antigenic cross reactivity between human HBV and duck hepatitis B virus antigens.

Duck hepatitis B virus infection, aflatoxin B1 and liver cancer in ducks.

The association between chronic infection by hepadnaviruses isolated from human (HBV), woodchuck (WHV), ground squirrel (GSHV) and development of hepatocellular carcinoma (HCC) in their respective hosts is well established (reviewed in [11, 15, 17]). By contrast, the association of duck hepatitis B virus (DHBV) infection with HCC is less documented. Pekin ducks congenitally infected with DHBV and followed for several years throughout the world do not develop liver tumors: HCC has been found only in domestic ducks from a single area of China, Qidong. Several factors such as DHBV carrier rate, breed and age of ducks, subtype of DHBV and environmental carcinogens are suspected to contribute to this striking difference between the geographical repartition of liver cancer in DHBV-carrier ducks. In this brief review we will consider successively the role of these different factors in duck liver oncogenesis.