Over
years or decades, chronic hepatitis B virus (HBV) infection can lead to progression
of liver disease, potentially leading to cirrhosis
or hepatocellular carcinoma (HCC).
In
the first study, researchers from Hong Kong assessed
the link between presence of hepatitis B “e” antigen (HBeAg) and HCC. Usually,
HBeAg indicates that HCV is actively replicating. However, some strains of HBV
with precore/core promoter mutations replicate without expressing HBeAg. After
infection, patients may experience HBeAg seroconversion, either spontaneously
or due to anti-HBV therapy.
As
background, the investigators noted that HBeAg positivity is associated with increased
risk of HCC during long-term follow-up, but at the time of HCC development, more
than 70% of patients already had experienced HBeAg seroconversion. The present
study aimed to identify factors associated with development of HCC in patients
after spontaneous HBeAg seroconversion.
The study included all 602 patients
(58% men) with documented spontaneous HBeAg seroconversion seen at the hepatitis
clinic at QueenMaryHospital in Hong
Kong. Subjects were monitored every 3-6 months for acute hepatitis
exacerbation and development of HCC; the median follow-up period was 8.8 years
(range 0.6-23.8 years). In patients aged 40-65 years with HCC, the time of e-seroconversion
was compared to age-matched control
subjects without HCC.
Results
19 patients developed HCC, diagnosed
at a median interval of 4.3 years after HBeAg seroconversion (range 1.4-14.4 years).
Significant risk factors for HCC
by log-rank test included:
patient age at e-seroconversion;
presence of underlying cirrhosis
at the time of e-seroconversion;
peak alfa fetoprotein (AFP) levels
before and after e-seroconversion;
post-seroconversion median alanine
aminotransferase (ALT) level.
In a multivariate analysis, both
cirrhosis (OR 4.128; P = 0.017) and age at the time of e-seroconversion (OR 1.099;
P < 0.001) remained significant factors associated with risk of HCC.
HCC patients had a significantly
higher median age at the time of e-seroconversion compared to subjects without HCC (46 vs 42 years,
respectively: P = 0.049).
The cumulative HCC incidence at
5 and 10 years from the time of e-seroconversion for different age groups is shown
in the table below.
The 15-year cumulative incidence
of HCC in patients with cirrhosis after spontaneous HBeAg seroconversion was 32%,
compared with 2% in patients without
cirrhosis (P < 0.001).
The
investigators concluded that, “In patients undergoing spontaneous HBeAg seroconversion,
older age [at time] of seroconversion and underlying cirrhosis were significant
factors associated with increase risk of HCC development.”
HBV Mutations and Viral Load
In
a related study, researchers examined whether HBV genotype or precore/core promoter
variants were independent risk factors for HCC. They also sought to determine
if there was a cut-off HBV DNA level that could distinguish patients at high or
low risk for developing HCC. This analysis included 248 HCC patients and 248 control
subjects matched for sex, age, and HBeAg status.
Results
Compared with controls, HCC patients
had a higher prevalence of genotype C (57.4% vs 71.7%, respectively; P = 0.001;
OR 1.9).
HCC patients were also more likely
to have core promoter mutations (66.8% vs 88.1%, respectively; P < 0.001; OR
3.7).
The prevalence of precore mutations
was comparable in the 2 groups.
In a multivariate analysis, presence
of core promoter mutations was the only independent risk factor for HCC (P <
0.001).
Further analysis revealed that
core promoter mutations were associated with a specific sequence, V1753, which
is known to be associated with HCC.
There was no lower limit of HBV
DNA level that conferred lower risk of HCC.
In
conclusion, the researchers wrote, “Core promoter mutation was an independent
risk factor for HCC. Its relationship with T1753 with respect to hepatocarcinogenesis
needs further investigations. There was no HBV DNA level associated with lower
risk for HCC.”
Department
Of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong-S.A.R.,
China; Department Of Clinical Molecular Informative Medicine, Nagoya City University
Graduate School Of Medical Sciences, Nagoya, Japan; Department Of Surgery, University
of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong-S.A.R., China.
05/11/07
References
J Fung,
C L Lai, D K Wong, and others. Large population study on the natural history of
spontaneous hepatitis B e-antigen seroconversion: risk of hepatocellular carcimoma.
42nd Annual Meeting of the European Association for the Study of the Liver (42nd
EASL). Barcelona, Spain. April 11-15, 2007.
M
F Yuen, Y Tanaka, N Shinkai, and others. Role of HBV genotypes, core promoter/precore
mutations and HBV DNA levels on hepatocellular carcinoma. 42nd EASL
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