Hepatitis B virus infection (HBV) is an important health problem worldwide, with a significant rate of chronic infection, which can lead to cirrhosis and hepatocellular carcinoma (HCC). Increased age is an important determinant of progression to cirrhosis and HCC, possibly because age is a crude measure of the duration of HBV infection. Increasing age is associated with changes in liver structure, blood flow and function and with reduced response to injury, impaired regeneration and increased mortality in acute liver disease. Age has been identified as a co‐factor in several chronic liver diseases including chronic hepatitis C infection (HCV). Available evidence suggests differential ageing of various intrahepatic cell types in different liver diseases and the ageing process may be more complex in the liver than originally thought. Telomeres are DNA structures located at the end of each chromosome, which protect the underlying coding DNA from breaks and fusions and shorten with increasing age. Both DNA damage and cell proliferation lead to progressive telomere shortening, which ultimately leads to cell cycle arrest and a state of replicative senescence. Persistent HCV and HBV infections lead to cell cycle arrest, providing a favourable environment for viral replication. Evidence suggests that progressive telomere shortening occurs with advancing stage of liver disease in HBV and specifically from cirrhosis through large cell dysplasia to small cell dysplasia and to HCC. Whether cell cycle arrest leads to a senescent‐like state or whether this is the result of oxidative stress is unknown. Unpublished data using cell cycle phase markers in chronic HBV infection reveal that hepatocytes, which support HBV replication, are arrested in G1, which is mediated by hepatocyte p21 expression. I hypothesise that: 1. In normal liver tissue, different cell types age at different rates and this is altered during disease; 2. Hepatocyte senescence plays a significant role in the natural course of chronic HBV infection and underlies HBV antigen expression. I developed and optimised large volume Q‐FISH methodology to measure telomere length and nuclear size in a variety of intrahepatic cell lineages. In normal liver tissue, cholangiocytes had longer telomeres compared with all other intrahepatic lineages over a wide age range. Hepatocytes did not show any age‐related telomere shortening, in contrast to Kupffer and hepatic stellate cells. In chronic HBV infection, all hepatocytes had shortened telomeres when compared to age and sex‐matched controls consistent with accelerated ageing. HBV replication was confined to those hepatocytes with longer telomeres, suggesting that HBV entry or replication is less efficient in older hepatocytes and compatible with the fall in serum HBV DNA and HBsAg titre seen with advancing age. There may be two populations of hepatocytes in chronic HBV infection; hepatocytes that are growth arrested with short telomeres not supporting HBV replication and biologically 'younger' hepatocytes with longer telomeres that do support HBV replication. The change in cellular HBV antigen localisation with disease progression is also explained by age related changes in HBV expression. Nuclear Hepatitis B core antigen expression (HBcAg), characteristic of the early immune tolerant phase of infection, was associated with the longest telomeres, while cytoplasmic HBcAg expression was associated with shorter telomeres. Furthermore, the total number of hepatocyte telomeres fell with increasing fibrosis stage. Hepatocyte nuclear size, a marker of senescence, increased as HBcAg expression shifted from nucleus to cytoplasm; and p21, another senescence marker, never co‐localised with HBcAg expression. These results suggest that the location and production of HBV antigens are related to increased functional hepatocyte age and the onset of cellular senescence.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:680959 |
| Date | January 2015 |
| Creators | Tachtatzis, Phaedra Maria |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=228557 |
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