Influence of viral and host characteristics on clinical outcome of hepatitis B / Chook Jack Bee
Hepatitis B is a global health problem, affecting >2 billion people worldwide. Chronicity develops in >90% of neonates infected by hepatitis B virus (HBV). After several decades of the infection, about a-quarter-to-half may progress to liver cirrhosis and hepatocellular carcinoma (HCC). In...
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| Format: | Thesis |
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2013
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| Online Access: | http://studentsrepo.um.edu.my/5617/ http://studentsrepo.um.edu.my/5617/1/Chook_JB_2013_PhD_thesis_Faculty_of_Medicine_25June2013.pdf |
| Summary: | Hepatitis B is a global health problem, affecting >2 billion people worldwide.
Chronicity develops in >90% of neonates infected by hepatitis B virus (HBV). After
several decades of the infection, about a-quarter-to-half may progress to liver cirrhosis
and hepatocellular carcinoma (HCC). In contrast, more than 90% of people infected
during adulthood may clear the infection, resulting in acute self-limiting hepatitis. Both
virus and host may influence clinical outcome of the infection. Basal core promoter
(BCP; A1762T/G1764A) and precore stop codon (G1896A) mutations have been
commonly associated with cirrhosis and HCC, whereas wild-types of these mutations
with acute hepatitis. These associations have been inconsistent; the disease progression
may have been affected by other non-viral factors. Host iron status could be one of the
important factors; iron overload increases risk of cirrhosis and HCC. It has rarely been
considered in chronic hepatitis B studies. The present study is divided into two sections.
The aim of the first section is to investigate the influence of viral genomic variations
and host iron markers (serum iron and serum ferritin) on progression to cirrhosis and
HCC, whereas the second section to identify potential viral genomic variations
associated with chronicity based on in silico observation. Overlapping polymerase chain
reaction (PCR) was applied to amplify viral genomic fragments. The fragments were
then sequenced and assembled. Sera were also sent to clinical laboratory for testing of
the iron markers. To search for candidate nucleotides associated with cirrhosis,
comparative sequence analysis was performed in 20 cirrhotic cases and 20 controls,
whereas for HCC, the analysis was done in 21 HCC cases and 24 controls. The most
potential viral marker was then applied in larger chronic hepatitis B populations,
including 216 controls, 78 cirrhosis and 39 HCC cases. Binary logistic regression
analysis showed that older age, cigarette smoking, family history of cirrhosis/HCC,
HBV precore wild-type, serum iron and serum ferritin were associated independently
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with HCC, whereas older age, male gender, Malay ethnicity, precore wild-type, serum
iron and serum alanine aminotransferase (ALT) with cirrhosis. To search for candidate
nucleotides associated with chronicity, comparative sequence analysis was conducted in
177 acute cases and 1,149 chronic cases. Binary logistic regression coupled with
Bonferroni-correction identified four novel viral variants (G1171, T1785, A1786 and
T3112) independently associated with acute hepatitis. These variants are located in
enhancer-I-X-promoter and S promoter regions, mutations in which result in reduced
viral replication and release. In conclusions, older age, precore wild-type and serum iron
markers may increase the risk of progression to cirrhosis and HCC, but not to NAFLD.
Cigarette smoking, male gender, Malay ethnicity and high serum ALT should also be
considered. The present study has also identified novel variants (G1171, T1785, A1786
and T3112) highly specific for acute self-limited infection. These putatively replicationdefective
variants may be responsible for lower rate of chronicity in some cases of HBV
infection. Further in vitro and in vivo investigations are required to confirm this
hypothesis. |
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