May 16th
Abstract ID: M1710
V.W.
Wong, A.Y. Cheng, P. Tong, W. So, W. Chan, F.C. Chow, H.L. Chan, J.J. Sung, J.
Chan
Background
Chronic
hepatitis C is associated with insulin resistance and type 2 diabetes mellitus.
The association is more controversial among hepatitis B patients. This study
aims to investigate the metabolic profile and clinical course of diabetic
patients with chronic hepatitis B (CHB).
Methods
2931
Hong Kong Chinese with diabetes underwent comprehensive examination for
diabetic control and complications at a university hospital from February 1995
to April 1999. They were then assessed prospectively for mortality and major
cardiovascular events.
Results
After
excluding 93 patients with type 1 diabetes mellitus, 2838 patients were
included in the current analysis. The mean age at baseline was 59.7 years (SD
12.9). 1669 (58.8%) patients were female. 286 (10.1%) patients had CHB. CHB
patients had earlier onset of diabetes than HBsAg
negative controls (mean age 51.0 versus 53.7 years, p = 0.0002). More CHB
patients had glycosylated hemoglobin above 8% (40.2%
versus 34.2%, p = 0.04). On the other hand, CHB patients had lower systolic
blood pressure (134 versus 137 mmHg, p = 0.05), lower total cholesterol level
(5.2 versus 5.5 mmol/l, p = 0.001), lower
LDL-cholesterol (3.3 versus 3.5 mmol/l, p = 0.01) and
lower triglycerides (1.5 versus 1.8 mmol/l, p =
0.0003). Both groups had similar body mass index and hip-waist ratio. Diabetic
retinopathy is more common among CHB patients (28% versus 23%, p = 0.03). At a
mean follow-up of 3.5 years (range 1.7 to 5.9 years), mortality was 7% among
CHB patients and 4% among controls (p = 0.02). However, the excessive deaths
were largely due to liver failure and hepatocellular carcinoma among CHB
patients (3.8% versus 0.3%, p < 0.0001). There is no difference in macrovascular complications and cardiovascular events
between the two groups.
Conclusions
CHB
patients have earlier onset of diabetes and poorer diabetic control. This
results in increased prevalence of diabetic retinopathy. The better blood
pressure control and more favorable lipid profile among CHB patients provide
protection against macrovascular complications.
Abstract ID: M916
c. cengiz, n. turhan, m. akdogan, d. oguz, s. kacar
Introduction
There
is conflicting data on whether therapy for chronic Hepatitis B Virus (HBV)
infection reduces the risk of developing hepatocellular carcinoma (HCC). HBV X
protein (HBx), proliferating cell nuclear antigen
(PCNA) and p53 protein are known to play a role in HBV related hepatocarcinogenesis. The impact of HBV therapy on these
histological markers has yet to be addressed.
Aim
To
evaluate the histological expression of HBx, PCNA and
p53 in a cohort of chronic HBV patients treated with interferon (IFN) and /or
lamivudine (3TC).
Methods
Thirty
HBV monoinfected, antiviral therapy naive individuals, 18 HBe
antigen negative (HBe Ag -) and 12 positive (HBe Ag +) were treated with IFN alfa-2a 9 MU 3 x
weekly + 3TC 100mg daily (n = 23) or 3TC
alone (n =7) for 12 months. Liver biopsies were performed pre and post
antiviral therapy. End- of-treatment virological response (ETVR) was determined
for each patient. Biopsies were stained for HBx, PCNA
and p53 using monoclonal antibodies, and PCNA index (number of PCNA expressing
hepatocytes per 1000 hepatocytes) post therapy compared to baseline (BL) was
evaluated.
Results
Mean
age of cohort was 35, 17 male, all were Caucasian. No subject had cirrhosis. HBx was expressed in 5/30 (17%) of BL biopsies, 4/5 HBx (+) biopsies were from HBe Ag
(-) subjects. No biopsy was p53 (+). All biopsies (+) for HBx
exhibited BL PCNA scores above the mean. Loss of HBx
after HBV therapy (n = 3) was
associated with decrease in PCNA index. Subjects achieving an ETVR (n = 25) had
a significant decrease in PCNA index post therapy compared to baseline (p<
0.005), there was no significant difference between pre and post therapy PCNA
index in those not attaining an ETVR. Large cell dysplasia
(LCD) was observed in 8/30 (27%) of BL biopsies and in 3/5 (60%) of HBx (+) biopsies. LCD was associated with a higher BL PCNA
index (p< 0.05). Persistant HBx
expression post therapy (n = 2) was associated with LCD on BL biopsy, and failure
to achieve ETVR or to reduce PCNA index.
Conclusion
We
conclude that HBx expression is commoner in HBe Ag (-), precore mutant
subjects and is associated with a higher PCNA index as well as LCD. Achieving
an ETVR is associated with decrease in PCNA index. HBV therapy may provide HBx antigen loss. Further studies are indicated to
determine if individuals with decreased PCNA index and/or loss of HBx expression following
therapy are at lower risk of developing HCC.
Abstract ID: M930
C.
Madden, B. Slagle
Objective
The
hepatitis B virus X protein (HBx) is necessary for
the establishment of infection in mammals and significantly increases the level
of virus produced in vitro. HBx has also been shown to influence apoptosis. The purpose of this study was to identify the
impact of HBx expression on molecular pathways
related to cellular proliferation, senescence, necrosis, and apoptosis.
Methods: We utilized membrane arrays to examine the
influence of HBx expression on 96 key genes related
to cell stress and toxicity. Total RNA
was isolated from HepG2 cell cultures transiently transfected
with an HBx expression or control plasmids.
Results
Of
the 96 genes analyzed, the expression level of damage inducible transcript 3
(DDIT3/GADD153/CHOP) exhibited the most dramatic increase (approximately
4-fold) due to the expression of HBx. DDIT3 is a pro-apoptotic stress response
protein produced in response to DNA damage, nutrient deprivation, or the
accumulation of unfolded proteins.
Consistent with the induction of DDIT3, intracellular localization
studies performed with HBx and the green fluorescent
protein (GFP) indicated that HBx/GFP fusion proteins
form cytoplasmic inclusions in transfected
HepG2 cell cultures. The precise nature
of these inclusions is under investigation but they may represent aggregates of
misfolded protein that are responsible for the
increase in DDIT3.
Conclusions: The induction of DDIT3 may have important
consequences for viral replication.
DDIT3 encodes the C-EBP-homologous protein (CHOP), a stress response
transcription factor. Although CHOP is
often considered a pro-apoptotic tumor suppressor protein, it both positively
and negatively regulates signaling by members of the C-EBP and AP-1 family of
transcription factors. The ability of HBx to increase production of CHOP may serve as an
important regulator of viral gene expression.
Abstract ID: M1224
V. Warren, S. Tong, H. Liu,
K.E. Kim
Introduction
Asian Americans have the
highest rates of hepatitis B in the United States. Hepatitis B immunization has decreased the
incidence of infection. Our Chicago Asian immigrant community based hepatitis B
screening program have identified approximately 10% positivity
rates for hepatitis B surface antigen.
However, studies to date have not reported the prior immunization status
in Asian community based hepatitis B screening programs.
Between 2001- 2003, 1019
Asian immigrants in the Chicago and metropolitan area were screened for
hepatitis B (Chinese,Vietnamese, Cambodian, Lao,
Korean, Indian, Pakistani, Ethiopian and Somali).
Methods
All screenings were
performed in community based settings and were linguistically specific. All participants completed a translated
survey on risk factors, health beliefs and previous immunizations.
94 persons were HbsAg+ for an average rate of 9.23%. (Men 13%,Women
7%). 53% were immune (anti-HBs+); 37% had no immunity (anti-HBs
negative). 54% (546) were antiHBs+. 64% of persons with immunity to HBV reported
no recollection of receiving HBV vaccine.
5% said they had had a past diagnosis of hepatitis. Table 1 reports the breakdown of immunization
history in those positive for HBsAg.
In our study population,
those aged 19-35 had both the highest rates of both HBsAg
positivity and previous hepatitis B immunization
reporting. The concern for this young
Asian population is the risk of absent follow up and needed screening and/or
treatment. Since greater than 60% of all
Asian Americans are foreign born, immigrating from regions highly endemic for hepatitis
B and where a new emphasis on immunization is increasing, this study highlights
the need for aggressive screening despite immunization history. Previous immunization in Asian Americans
should not deter screening and evaluation for hepatitis B risk.
Table 1 Sero-prevalence of HBsAg by age group and immunization history
|
Age
Group n |
HBsAg + n
(%) |
Reporting No Vaccine n (%) |
Reporting Vaccine n (%) |
|
<18 32 |
1
(3.13) |
21 (65.6) |
11 (34.7) |
|
19-35 209 |
34
(16.27) |
147 ( 70.3) |
62 (29.7) |
|
36-45 251 |
28
(11.16) |
191 (76.1) |
60 (24) |
|
46-55 195 |
18
(9.23) |
158 (81.0) |
37 (19) |
|
56-65 215 |
8
(3.72) |
153 (71.2) |
62 (28.8) |
|
>65 105 |
5
(4.76) |
79 (75.2) |
26 (24.8) |
|
No age recorded 12 |
|
|
|
Abstract ID: M1223
H. Liu,
V. Warren, K.E. Kim
Introduction
Asian Americans have the
highest rates of hepatitis B in the United States. One in ten Asian Americans
have chronic hepatitis B; 25% of those with chronic hepatitis B will die from
complications of the disease, including cirrhosis and hepatocellular carcinoma.
Within certain Asian communities, hepatocellular carcinoma has been reported to
be up to 12 times more common than in Caucasian Americans, representing the
greatest cancer health disparity in the United States. Despite the availability
of effective hepatitis B vaccines, studies of hepatitis B susceptibility within
disaggregated Asian immigrant communities have not been well reported.
This study aims to determine the prevalence and susceptibility of hepatitis B between
7 different Asian immigrant communities in the Chicago metropolitan region.
Methods
This prospective, convenience sampled study utilized lay health
educators to provide education coupled with community based hepatitis B screening
programs in 7 separate Asian immigrant community centers. Clients who
regularly attended community center events were asked to participate in the
study. All screening programs were carried out in their native languages
which included Korean, Chinese, Vietnamese, Laotian, Cambodian and
Indo-Pakistani languages.
Results
A total of 800 clients were
screened. 59% were women; the age range was 31-70, with the mean of
47. Overall, 10% were HBsAG-positive, 53% were HBsAB-positive and 37% were neither HBsAG/HBsAB-positive
(susceptible group). There were wide variations in hepatitis B markers
between Asian ethnic groups(see Table 1)
Hepatitis B is an extremely
infectious, yet preventable disease. Immigrants from Asia are at
highest risk for chronic hepatitis B and early death. This study shows
the variations in hepatitis B prevalence, immune status and susceptibility
within disaggregated Asian immigrant communities, and addresses the need for
tailored, ethnic specific hepatitis B education, prevention and intervention
within and between communities. Asian Americans are the most rapidly growing
immigrant population in the US, and with greater than 60% of Asian Americans
being foreign-born, early screening and prevention for hepatitis B must be
universally instituted.
|
Table
1: Hepatitis B Screening Serology by Asian Ethnicity |
|
|
|||||
|
|
Korean |
Chinese |
Vietnamese |
Laotian |
Cambodian |
Pakistani |
Indian |
|
HBsAg+ |
5.70% |
13.90% |
11.50% |
13.60% |
7.00% |
12.50% |
1.00% |
|
HBsAb+ |
52.50% |
54.60% |
63.10% |
50% |
55.80% |
25% |
7.60% |
|
Susceptible |
41.80% |
31.50% |
25.40% |
36.40% |
37.20% |
62.50% |
92.30% |
Abstract ID: M1225
W. Kijkunasathian,
P. Tangkijvanich, P. Kongkam,
P. Komolmit
BACKGROUND
Several
practice guidelines have been proposed to assist physicians in management of
chronic hepatitis B patients. Most of them recommend that liver biopsy and
treatment should be performed in patients with ALT levels > 2*ULN. However,
such management in patients with ALT levels of 1-2*ULN is still controversial.
METHODS/AIMS
A
cross-sectional analytic study was performed to characterize the histologic features of the chronic hepatitis B patients
with elevated ALT levels of 1-2*ULN and levels > 2*ULN according to the
Knodell histologic activity index and to determine
whether there were any predictors of hepatic necroinflammation
and fibrosis.
RESULTS
Of
104 patients, 35 patients had ALT levels of 1-2*ULN (mean ALT 1.5*ULN). 69
patients had ALT levels > 2*ULN (mean ALT 4.4*ULN). Mean necroinflammatory
scores and fibrotic scores in the first group were 4.26(2.17) and 1.71(1.38),
respectively and the latter group were 4.58(2.26) and 1.51(1.16), respectively.
13 patients (38.2%) in the first group had necroinflammatory
scores > 3 and fibrotic scores >1. There were no statistically
significant associations among age, sex, BMI, HBeAg status, HBV-DNA, bilirubin
and albumin predictive of liver histology.
SUMMARY
There
were no differences in liver histology between patients with ALT levels of
1-2*ULN and levels > 2*ULN and no statistically significant associations
among characteristic of patients, virology and biochemistry to predict liver
histology. CONCLUSION: ALT level alone can not be used to predict necroinflammatory and fibrotic indices in chronic hepatitis
B patients.
|
|
ALT < 2x (n=35) |
ALT > 2x (n=69) |
p value |
|
Mean
necroinflammatory scores |
4.26(2.17) |
4.58(2.26) |
p = 0.488 |
|
No.
of patients with
necroinflammatory scores > 3 |
13 (38.2%) |
33 (47.1%) |
p = 0.391 |
|
Mean
fibrotic scores |
1.71(1.38) |
1.51(1.16) |
p = 0.450 |
|
No.
of patients with
fibrotic scores > 1 |
13 (38.2%) |
18 (25.7%) |
p = 0.190 |
Abstract ID: M1228
P. Tangkijvanich,
V. Mahachai, P. Komolmit,
J. Fongsaran, A. Theamboonlers,
Y. Poovorawan
AIMS
The role of hepatitis B virus
(HBV) genotypes on the clinical features and prognosis of patients with hepatocellular carcinoma (HCC) are currently unknown.
The aim of the present study was to evaluate the distribution of HBV genotypes
and their clinical relevance in Thai patients.
METHODS
Patients with genotype C
had a higher positive rate of HBeAg and exhibited earlier progression of
cirrhosis and HCC than those with genotype B. However, there were no
differences in the risk of developing HCC and its prognosis between patients with
these genotypes.
BV genotypes were
determined by PCR-RFLP in stored sera of 93 asymptomatic carriers, 103 patients
with chronic hepatitis, 60 patients with cirrhosis and 76 patients with HCC.
The clinical data were analyzed in relation to the HBV genotype. RESULTS: HBV
genotypes C and B were predominant in Thailand, accounting for 73% and 21%,
respectively. The distributions of genotypes B and C were similar in HCC
patients compared to the other groups. Genotype C was significantly more common
in HCC patients who were under 40 years old than genotype B (18% vs. 0%,
P=0.03), but was significantly less common in patients older than 60 years (26
% vs. 56.5%, P=0.01). The positive rate of HBeAg in patients with genotype C
was significantly higher than that in patients with genotype B (71.6% vs.
44.4%, P=0.03 in chronic hepatitis; 56.8% vs. 11.1%, P=0.01 in cirrhosis).
There were no differences between HCC patients with genotypes B and C regarding
of tumor staging by CLIP criteria and the overall median survival. Multivariate
analyses showed that HBV genotype was not an independent prognostic factor of
survival in HCC patients.
HBV genotypes were
determined by PCR-RFLP in stored sera of 93 asymptomatic carriers, 103 patients
with chronic hepatitis, 60 patients with cirrhosis and 76 patients with HCC.
The clinical data were analyzed in relation to the HBV genotype. RESULTS: HBV
genotypes C and B were predominant in Thailand, accounting for 73% and 21%,
respectively. The distributions of genotypes B and C were similar in HCC
patients compared to the other groups. Genotype C was significantly more common
in HCC patients who were under 40 years old than genotype B (18% vs. 0%,
P=0.03), but was significantly less common in patients older than 60 years (26
% vs. 56.5%, P=0.01). The positive rate of HBeAg in patients with genotype C
was significantly higher than that in patients with genotype B (71.6% vs.
44.4%, P=0.03 in chronic hepatitis; 56.8% vs. 11.1%, P=0.01 in cirrhosis). There
were no differences between HCC patients with genotypes B and C regarding of
tumor staging by CLIP criteria and the overall median survival. Multivariate
analyses showed that HBV genotype was not an independent prognostic factor of
survival in HCC patients.
CONCLUSION
Patients with genotype C
had a higher positive rate of HBeAg and exhibited earlier progression of
cirrhosis and HCC than those with genotype B. However, there were no
differences in the risk of developing HCC and its prognosis between patients
with these genotypes.
Abstract ID: M1231
P. Ozkal,
H. Ilgin Ruhi, M. Akdogan, S. Kacar, N. Sasmaz
Introduction
Chronic
viral hepatitis is the main cause of chronic liver disease, cirrhosis and
hepatocellular carcinoma in the world. Hepatitis B virus (HBV) has mutagenic
effects on host cell. Hepatitis B virus may be showing these mutagenic effects
by its viral proteins or integrating into host DNA. The aim of this study is to
detect the genotoxic effects of the hepatitis B
virus (HBV) to the host DNA.
Material and Method
Thirty-one patients with chronic hepatitis B (CHB), 20 with HBV carriers
and 20 healthy controls were included in this study. Peripheral
blood lymphocytes of 31 chronic hepatitis B patients and 20 chronic HBV
carriers were cultured to make cytogenetic evaluation
by observing chromosome breakage and cytologic
evaluation by micronucleus (MN) test. Their results were compared with healthy
controls. For each individual 100 metaphase chromosome spreads were analysed. 190-1091 binucleated
cells were observed and for each individual MN were scored.
Results
Our
results showed a significantly higher frequency of chromosome breaks in patients
with CHB and in HBV carriers than control group (p=0,031 and p=0,007,
respectively). There was no difference between CHB patients and HBV carriers
(p>0.05). Moreover we did not find any difference at MN scores between each
groups (p>0.05). No correlation was found between the lenght
of HBV positivity and MN scores&chrosome
breaks (p>0.05).
Based
on this data, we concluded that chronic HBV patients and carriers have
chromosomal instability and HBV carriers are as important as patients because
of their same chromosome breakage frequency.
Abstract ID: M940
Y.
Tanaka, F. Kanai, K. Tateishi, T. Ikenoue,
Y. Asaoka, B. Guleng, J. Amarsanaa, M. Ohta, J. Imamura,
T. Kawabe, M. Omata
Background/Aim
Hepatitis B virus (HBV) is closely
associated with the development of acute or chronic hepatitis and
hepatocellular carcinoma (HCC). Hepatitis B virus X protein (HBx), one of four ORFs of HBV, is
considered to be a major factor responsible for hepatocarcinogenesis,
since the expression of HBx induces HCC in certain
strains of transgenic mice. HBx was also shown to
stimulate cytoplasmic transcription indirectly by
activating cellular signal transduction pathways, including AP-1. AP-1 can
display its oncogenic effects by regulating genes
involved in cell proliferation, differentiation and apoptosis. However, the
mechanism of AP-1 activation by HBx remains poorly
understood. To investigate the molecular mechanism of HBx-mediated
AP-1 activation, we tried to identify new host factors which interact with HBx. Methods: We constructed a mammalian
expression vector encoding HBx with carboxyl-terminal
myc and flag tag separated by a cleavage site for the
TEV protease, transiently transfected 293T cells with
the vector, and purified the tagged HBx with its
binding proteins from the cell lysate by affinity
purification. After proteins were eluted, they were separated by SDS-PAGE,
silver stained and analyzed by nano LC/MS/MS. In vivo
and In vitro interactions were confirmed by immunoprecipitation
and GST pull-down assay, respectively. Interacting domain of HBx was determined by deletion constructs. Luciferase assay was performed to investigate the effect of
the AP-1 activation. Results: We identified COP9
(constitutive photomorphogenesis 9) signalosome (CSN) subunit 3 and 4 as HBx
interacting proteins by mass spectrometry. We also detected CSN subunit 5, Jab1
(Jun activation domain-binding protein 1), as a novel cellular target of HBx. HBx binds to Jab1 in vivo
and in vitro, and analysis of HBx deletion constructs
revealed that amino acid 30 to 125 of HBx was
responsible for the binding to Jab1. Furthermore, co-transfection
of HBx and Jab1 showed potent AP-1 activation
compared with HBx mutant lacking Jab1 interacting
domain (HBx 61-154). Conclusions: These results
suggest that Jab1 binds to HBx and facilitate HBx-mediated AP-1 activation. These findings are helpful to
elucidating the underlying mechanisms of viral hepatitis and hepatocarcinogenesis. Acknowledgement: This is a
collaborative research with Dr. Tohru Ichimura and Dr. Toshiaki Isobe
(Department of Chemistry, Graduate School of Science, Tokyo Metropolitan
University, Tokyo, Japan).
Abstract ID: M924
U.H.
Iloeje, MD, H. Yang, MSc,
J. Su, MD, MSc, C. Jen, MSc,
E. Kuo, MD, S. You, PhD, C. Chen, PhD
Introduction
Treatment guidelines exclude
chronic hepatitis B patients with normal serum ALT from therapy. This study was carried out to examine the
risk of HCC in this population of patients with emphasis on the role of serum HBV
DNA level.
Methods
A cohort of 3,851
participants with chronic HBV infection was recruited from seven townships in
Taiwan between 1991 and 1992. Cohort
entry serum samples were tested for HBsAg, HBeAg, HBV
DNA by PCR, and serum ALT. The diagnosis
of HCC was ascertained through data linkage with computerized profiles of the
National Cancer Registry and Death Certification System in Taiwan. Multivariable adjusted relative risks (RRadj) were derived using Cox proportional
hazard models.
Results
Overall, during 43,993
person-years of follow-up, 176 patients were newly diagnosed with HCC among the
3,851 participants. Of the 3,851
participants, 3,270 (85%) were seronegative for
HBeAg, of which 1121 (34%) had serum HBV DNA level ³104
copies/mL and 1052 (94%) of them had a normal serum ALT level. 581 participants (15%) were HBeAg positive of
which 557 (96%) had serum HBV DNA ³104
copies/mL at cohort entry and 463 (83%) of them had normal serum ALT
levels. There was a dose dependent relationship
between HBV DNA and HCC risk in people with normal serum ALT variably defined
as either <1 x ULN or <2 x ULN.
Adjusted Relative Risk of Liver Cancer for Various Serum HBV DNA and
ALT Levels
|
HBV DNA Levels |
ALT |
No. of Subjects |
No. of Liver
Cancer Cases |
Adjusted
Relative Risk (95% CI) |
|
Undetectable（<3×102） |
<2´ULN |
939 |
15 |
1.0 |
|
<105 |
<2´ULN |
1870 |
39 |
1.5 (0.8-2.7) |