Posters – Sunday May 21, 2006 8:00AM
Hepatitis C
Epidemiology
Abstract S1039 – Emerging Importance of
Chronic Hepatitis C in Asian Americans
J. T. CHENG; C. Hsien; H. J. Sun;
M. J. Tong
Background
Studies on hepatitis C in the
Patients and Methods
A retrospective survey was conducted on 254 chronic
hepatitis C patients of Asian descent, who presented to the
Results
The mean follow-up period was 62.4 ± 54.2 SD months.
There were 135 males (53.1%) and 119 females. Mean age at presentation was 57.3
± 13.5 SD years. Among these 254 Asian American patients, 7.87% were born in
the
Conclusions
A majority of Asian Americans with chronic hepatitis C
reported a history of unsanitized medical injection
as the only risk factor for mode of transmission. Genotype 1 was the most
prevalent HCV genotype detected and appeared to have a lower rate of SVRs compared to other genotypes. HCC developed frequently
in our chronic hepatitis C patients of Asian descent.
Abstract S1040 –
Initial Content Validation of a Disease-Targeted Health-Related Quality of Life
(HRQOL) Instrument in Chronic Hepatitis B Virus (HBV) Infection: The HBQOL v1.0
B. M. Spiegel; P. Martin; R.
Bolus; S. Han; E. Esrailian; J. Talley; F. Kanwal
Background:
Despite the increasing realization that HRQOL is an
important outcome in chronic HBV, there are no validated, disease-targeted
instruments currently available. Investigators and clinicians must therefore
rely on either generic HRQOL instruments or traditional biological outcomes in
order to assess their patients’ health status. However, generic instruments may
fail to capture the most important components of HRQOL in HBV, and biological
outcomes fail to acknowledge patient perception. We therefore sought to develop
and validate a disease-targeted HRQOL instrument in HBV: the HBQOL v1.0. This
abstract describes the candidate items and scales resulting from our initial
content validation process.
Methods:
“Content validity” is the degree to which an
instrument contains a representative range of items and scales relevant to the
disease under study. If an instrument fails to measure attributes of importance
to patients with the targeted disease, then it will likely fail to accurately
measure HRQOL. In order to establish content validity for our instrument, we
initially conducted a search of MEDLINE for previously published HRQOL
instruments in both chronic viral hepatitis and other forms of chronic liver
disease. We then compiled a pool of items with relevance to HBV based on a
priori hypotheses and clinical judgment. We next convened a panel of 5 expert hepatologists experienced in HBV. Using a semi-structured
protocol, we first elicited the domains perceived by the panel as most relevant
in HBV. We then presented the items identified by the systematic review, and
asked the panel to comment on the content, breadth, and relevancy of the list. Finally,
in concert with 3 psychometricians, we developed a
conceptual model of the scales in HBV.
Results:
We selected 4 scales on the basis of their content
validity and potential responsiveness (i.e. ability to detect HRQOL change
after successful treatment): (1) Anticipation Anxiety/Psychological Well Being
(e.g. fear of developing cancer or cirrhosis), (2) Sexual Well Being/Intimacy
(e.g. transmission concern, impact on sexuality), (3) Disease Stigma/Social
Well Being (e.g. embarrassment, concern someone influential may find out,
shame), and (4) Daily Functioning (e.g. impact on diet or medication use).
Conclusions:
Four scales may capture HRQOL in HBV across a range of
psychological and social factors. The breadth and depth of biopsychosocial
symptoms in HBV highlights the significant HRQOL burden of this condition.
Ongoing research includes testing these scales with patient focus groups, and
prospectively measuring the construct validity and reliability of this evolving
instrument.
Abstract
S1041 – Sero-prevalence of hepatitis B and C in
hospital personnel
A. Hila;
R. Bouali; R. Belaaj; A. Belhadj; F. Khediri
Aim:
To assess the seroprevalence
of hepatitis B and C in hospital personnel during a hepatitis B vaccination
update campaign.
Methods:
A prospective study of 1895 personnel working at our
hospital Tunisa). These represent 95.2% of our total
personnel, which are 1992 people. The study was performed from June 2004 to
August 2004. Subjects included in this study were all personnel of the
hospital, including doctors, nurses, technicians, administrative and
environmental personnel. All study subjects had blood drawn for: antigen (Ag) HBs, antibody (Ab) anti-HBc, Ab anti-HBs
and Ab anti-HCV.
Mean age = 41 yo, range
20-60 years old; male to female ratio =
1.9 (990/905).
Results:
Prevalence of HBs Ag and
isolated Ab anti-HBc was
respectively 1.95% (37) and 4.6% (88). 14 subjects (0.74%) were positive for Ab anti-HCV.
860 personnel (45.3%) had no HBV markers, and were
thus vaccinated. Only 528 personnel (27.8%) were immune to HBV due to prior
immunization, and 240 of these had Ab anti-HBs titers < 100mU/ml, requiring a repeat dose of
vaccine. Of 65 cases with isolated Ab anti-HBc +, 50 (77%) developed Ab
anti-HBs after only 1 dose of vaccine. 6 out of the
15 non-responders (9.2 % of the total) were HBV DNA positive. Of the 14 cases
with Ab anti-HCV +, 3 had known chronic hepatitis C
and were previously treated with a sustained virologic response, 7 were RNA PCR
negative and 4 were positive.
Conclusion:
Prevalence of both hepatitis B and C in our hospital
are not higher than in the general population in our country. Most of cases
with isolated Ab anti-HBc positivity were immunized by disease (occult hepatitis:
blood DNA positivity < 10%). 50% of cases with + Ab anti-HCV had + RNA. This vaccination campaign allowed us
to vaccinate 45% of the personnel who were not immunized for hepatitis B.
W. Chen1; T. Wong; J. Heathcote;
M. Krahn
Background:
High body mass index (BMI) among patients with chronic
hepatitis C (HCV) is common as is hepatic steatosis on liver biopsy.
Objective:
To compare the prevalence of high BMI between patients
with HCV with that in the general population and to investigate predictors of
BMI in patients with HCV.
Methods:
HCV patients with age 25-64 years at first visit
between 1990 and 2004 were included. Medical records was reviewed
retrospectively to extract: age, gender, ethnicity, place of birth (for
immigration status), height, weight, alcohol abuse (> 50 g/d over 10 years),
heavy smoking (1 ppd > 10 years), mode of
transmission of HCV, estimated duration of infection (infection assumed to
start from birth if transmission mode unknown), genotype, liver biopsy
(fibrosis stage, presence of severe steatosis over 30%), and co-morbidity.
Data analysis:
Unpaired student t test was applied for continuous
outcomes; chi square test was applied for frequency outcomes; univariate and multivariable linear regression were
conducted to explore predictors for BMI.
Results:
1502 patients met inclusion criteria. Our patients
with HCV had a significantly higher prevalence of high BMI above 29.9 (23.2%
vs. 16.1%; P<0.001) than the general population (Statistics Canada 2001).
Among 446 patients with a documented liver biopsy, 301 patients were native
born and 145 patients were immigrants to
Conclusion:
High BMI (>29.9) is more prevalent among patients
with HCV than the general population in
C. A. Goulding;
R. Mc Manus; A. Murphy; G. S. Mac Donald; M. Dring;
J. Hegarty; S. Mc Kiernan; D. Kelleher
Background and Aims:
Toll-like receptors (TLRs)
are type I transmembrane proteins, which are highly
conserved through evolution. They activate innate immunity by recognizing and
binding to a wide variety of pathogenic substances. TLR7 and 8 both respond to
the synthetic imidazoquinoline compounds, known to
have anti-viral properties. TLR7 and probably TLR8 have also been demonstrated
to recognize single stranded viral RNA. This study aimed to assess the
involvement of inherited variations in TLR7 and 8 in determining disease
outcome in HCV infected individuals.
Methods:
223 women from Ireland were all exposed to HCV
genotype 1b from a single donor, and including 85 who had spontaneously cleared
the virus and 138 chronically infected, were genotyped for TLR 7 and 8
polymorphisms and haplotype tagging was performed.
The frequencies of these polymorphisms were then compared with disease activity
and severity.
Results:
TLR 7 and 8 genotypes were compared with HCV PCR
status, ALT levels and liver histology. There was no association between HCV
PCR status and the TLR polymorphisms. Of the 5 SNPs
examined in TLR8, wild types were associated with significantly worse fibrosis
for 2 SNP loci (TLR8C (C401T); 1.38 vs 0.78, p =
0.03, TLR8D (C426T); 1.39 vs. 0.70, p = 0.018). Degree of inflammation was
worse in TLR8B (A796C) wild type; 5.1 vs. 4.2, p = 0.008, and this group also
had higher ALT levels; 66 vs. 41, p = 0.018. TLR7B (C149T) was associated with
lower inflammation and 4.4 vs. 5.7, p = 0.015 ALT levels; 47.8 vs. 73.4, p =
0.014. On analysis of haplotypes, those containing
the minor allele for TLR8A or TLR8B had significantly less fibrosis (p = 0.025,
p < 0.01, respectively). Haplotypes containing the
minor allele for TLT7B had significantly lower inflammatory scores, p<
0.025. No haplotype was associated with viral
clearance.
Conclusion:
Consistent with prior functional data regarding viral
clearance, HCV viral clearance was not associated with any of the TLR 7 or 8 SNPs examined in this study. However, SNPs
in TLR 7 and 8 were associated with a lesser degree of hepatic inflammation and
fibrosis. Further functional characterisation of
these SNPs could provide important information on the
response of the host to HCV infection.
D. T. Lau; P. Fish; S. M.
Lemon; G. Michael
Alpha/beta Interferons (IFNs)
play important role in viral infections. HCV encodes proteins that block IFN
production and antagonize IFN actions to support viral persistence. The NS3/4A
protease of HCV disrupts viral activation of IRF-3, thereby attenuating IFN
production and IFN-stimulated gene (ISG) expression. [Foy et al, Science 2003;
300:1145-48].
In this study, we compared the transcriptional
profiles of ISGs among liver biopsy samples from
normal controls, HCV genotype-1 patients and patients with nonalcoholic fatty
liver disease (NAFLD) using Affymetrix HG-U95A Human GeneChips. Liver biopsy slides were also examined by immunofluorescence staining and confocal
microscopy analysis to define the subcellular
distribution of IRF-3, the extent of viral protein expression in hepatocytes,
and the composition of hepatic infiltrating immune cells.
HCV samples had significantly higher transcriptional
levels of ISGs associated with IFN such as OAS2,
MX1,ISG56 compared to controls and NAFLD (p<0.005). The level of IRF-3,
however, was similar in HCV and normal controls. HCV NS3 or NS5A proteins were
observed within focal areas of biopsy specimen and distributed in a perinuclear context within hepatocytes. IRF-3, though
abundant, was typically found in an inactive state as defined by its cytoplasmic-bound distribution in liver cells. Furthermore,
HCV infection was associated with specific CD3-positive T cell and plasmacytoid dendritic cell (PDC)
infiltrates in biopsy specimens.
Our results indicated that in chronic HCV, IRF-3
activation within infected hepatocytes is limited, which lends further evidence
of NS3/4A disruption of IRF-3 activation. Despite the lack of active IRF-3,
increased hepatic ISG expression in HCV infection was observed and was
correlated with the presence of immune cell infiltrates in liver samples.
Infiltrating immune cells could be an important source of alpha/beta IFNs that potentially influence hepatic ISG expression and
the outcome of HCV infection.
Abstract S1045 – Can we predict advanced
fibrosis in daily practice based on common blood tests?
R. Cheung; S. Currie; H. Shen;
T. Morgan; K. Hu; S. Ho; N. Brau;
E. Bini; T. Wright
Background:
Several indexes based on simple lab tests correlated
with liver biopsies read by expert pathologists in highly selected settings;
applicability to less stringent, community-based practice is unclear.
Aim:
To compare the specificity, sensitivity and ROC of
these indexes with liver biopsies in a cohort of 548 veterans with chronic
hepatitis C from 24 centers nationwide enrolled in a previous study.
Method:
All lab tests including interpretation of the liver
biopsy were done locally. The following indexes were calculated and correlated
with a 5-point fibrosis stage (F0-F4): platelet <100 x109/L, AAR (AST/ALT),
Pohl score (positive if AAR>1 and platelet <150x109/L), APRI
([AST/ULN]/platelet [x109/L]x100, and “Model 3” (log odds [predicting cirrhosis]=-5.56-0.0089
x platelet (x103/mm3)+1.26xAAR+5.27xINR) (Lok et al,
2005).
Results:
This cohort was predominately male with 24% blacks,
and distribution fibrosis stage of 0,1,2,3,4 were 11%,24%,28%,24%,13%,
respectively. When patients with mild fibrosis (F0-2) were compared to those
with advanced fibrosis (F3-4), the area under the ROC were 0.531 for platelet
count alone, 0.527 for
Conclusions:
|
Variable
Name |
Sensitivity |
95% CI
of Sensitivity |
Specificity |
95% CI
of specificity |
Positive
predictive value |
95% CI
of PPV |
Negative
predictive value |
95% CI
of NPPV |
||
|
|
0.217 |
0.163-0.282 |
0.798 |
0.749-0.839 |
0.391 |
0.301-0.489 |
0.630 |
0.582-0.676 |
||
|
Pohl score |
0.096 |
0.060-0.148 |
0.979 |
0.955-0.991 |
0.731 |
0.520-0.877 |
0.644 |
0.600-0.686 |
||
|
APRI<0.5 |
0.123 |
0.082-0.177 |
0.631 |
0.577-0.682 |
0.165 |
0.111-0.235 |
0.548 |
0.498-0.598 |
||
|
APRI>=1.5 |
0.376 |
0.307-0.443 |
0.904 |
0.867-0.932 |
0.697 |
0.601-0.780 |
0.708 |
0.663-0.750 |
||
|
APRI<1.0 |
0.397 |
0.330-0.468 |
0.204 |
0.163-0.251 |
0.228 |
0.186-0.276 |
0.363 |
0.296-0.435 |
||
|
APRI>=2.0 |
0.235 |
0.180-0.300 |
0.939 |
0.907-0.961 |
0.696 |
0.572-0.798 |
0.674 |
0.630-0.716 |
||
|
Model 3 <0.2* |
0.931 |
0.884-0.962 |
0.321 |
0.270-0.376 |
0.454 |
0.404-0.505 |
0.886 |
0.810-0.936 |
||
|
Model 3 >0.5 |
0.508 |
0.435-0.581 |
0.848 |
0.802-0.885 |
0.669 |
0.585-0.744 |
0.740 |
0.691-0.784 |
||
Abstract S1046 – C-Methacetin Breath Test as Quantitative
Liver Function Test in Patients with Chronic Hepatitis C: Continuous Automatic Molecular
Correlation Spectroscopy Compared to Isotopic Ratio Mass Spectrometry
O. Goetze; N. Selzner; M. A.
Kwiatek; M. Fried; T. Gerlach; B. Muellhaupt
Background and aims:
The 13C-methacetin breath test (MBT) has been
proposed for the non-invasive evaluation of hepatic microsomal
activity. Up to now, “gold standard” of stable isotope analysis is isotopic
ratio mass spectrometry (IRMS). The aim of this study was to test a new
continuous online automatic breath collection and analysis system in comparison
to IRMS in patients with chronic hepatitis C.
Methods: Sixteen patients with chronic
hepatitis C infection at different METAVIR fibrosis stages (F0, n=2; F1, n=6;
F2, n=0; F3, n=1; F4, n=7) were studied. After an overnight fast each subject
received 75 mg of 13C-methacetin dissolved in 100 ml of water. The 13C/12C
ratio of breath samples was analyzed over 120 min both by molecular correlation
spectroscopy with approximately one sample/3min (Oridion,
BreathID LTD, Israel) and by IRMS (Analytical
Precision Limited, AP2003, UK) every 10 min. Results were expressed as delta
over baseline (DOB [‰]) at each time interval and maximal DOB (DOBpeak[‰]). The association between both
methods was tested by linear regression analysis and by Bland-Altman analysis
after spline interpolation of the 13CO2
exhalation curves and for the detected peak height.
Results: A high positive linear association
between both analytical methods was observed (DOB: R2=0.95,
p<0.001, DOBpeak: R2=0.96,
p<0.001). For all DOB values the bias was -0.27 ‰ with a standard deviation
(SD) of 1.7 ‰ and limits of agreement of -3.7 ‰ and 3.2 ‰. For DOBpeak the bias was -0.97 ‰ with a SD of 2.6 ‰
and greater limits of agreement (-6.2 ‰ and 4.2 ‰), which were caused by a poor
peak detection with IRMS in 4 cases (figure).
Conclusions: The MBT obtained by
molecular correlation spectroscopy with continuous online automatic breath
collection and analysis system is an easy to operate method in patients with
chronic hepatitis C infection. It provides results comparable to the “gold
standard” isotopic ratio mass spectrometry and a better peak detection due to
the higher sampling frequency.
Abstract S1047 – 13C-Methacetin Breath
Test by Online Molecular Correlation Spectroscopy Compared to APRI and Liver
Biopsy for the Assessment of Fibrosis in Chronic Hepatitis C
O. Goetze; N. Selzner; A. Grau;
M. Fried; T. Gerlach; B. Muellhaupt
Background:
Stable isotope breath tests have been developed for
the non-invasive assessment of microsomal liver
function in patients with chronic liver disease. Among different tests
investigated, the 13C-methacetin breath test (MBT) appears to be
particularly suitable for the rapid assessment of hepatic functional reserve.
Aims:
To assess prospectively the performance of MBT in
patients with chronic hepatitis C infection using molecular correlation
spectroscopy with a continuous, online, automatic breath collection and
analysis system (Oridion BreathID,
LTD Israel) and to compare MBT outcomes with aspartate transaminase
to platelets ratio index (APRI) and with the METAVIR fibrosis score of a liver
biopsy specimen as a “gold standard”.
Methods:
60 patients (37 M, 48.1 ± 9.8 y., BMI 24.2 ± 3.6 kg/m2,
AST 1.5 ± 1.2, ALT 2.2 ± 2.0 x upper limit of normal, platelet count 173 ± 81 x
103/mm3) with chronic hepatitis C were studied (fibrosis
stage F0, n=8; F1, n=22; F2, n=11; F3, n=6; F4, n=13; obtained within six
months of MBT). After an overnight fast each patient received 75 mg of 13C-methacetin
dissolved in 100 ml of water. The 13C/12C ratio was
determined in each breath sample over 90 minutes by molecular correlation
spectroscopy (1sample/3min) as delta over baseline (DOB[‰]) and was expressed
as maximal (PDRpeak[%/h]) as well as
cumulative percentage dose of 13C recovered at 30 min (cPDR30[%]).
Results:
Both PDRpeak and
cPDR30 in patients with F≤1 were higher than in patients with
F≥2 (PDRpeak: 29.6 ± 9.8 vs 18.7 ± 11.9%/h, cPDR30: 9.7 ± 3.3 vs 5.7 ± 3.9%, p<0.001). Mean areas under the receiver
operating characteristic (ROC) curve of PDRpeak,
cPDR30 and APRI values were similar for F≥2 (0.82, 0.87, 0.77)
and for F≥3 (0.93, 0.95, 0.88). For F=4 area under ROC was higher for
cPDR30 than APRI (0.94 vs 0.81, p<0.05)
and similar for PDRpeak (0.91).
Conclusions:
MBT by continuous automatic molecular correlation
spectroscopy is an easy to use and effective method for assessing liver
fibrosis, with a better performance than APRI score for detection of severe
stages of fibrosis and with at least a similar performance to other reported
non-invasive surrogate marker of liver fibrosis.
Abstract S1048 – Increased
serum gammaglutamyltranspeptidase activity: a surrogate marker
of non alcoholic hepatic steatosis in chronic hepatitis C?
F. Benini;
L. Bercich; M. G. Pigozzi; L. Romanini; A. Reggiani; P. Donati; A. Pozzi; F.
Lanzarotto; C. Ricci; A. Lanzini
Predictors of poor response to antiviral treatment in
chronic hepatitis C include increased serum gammaglutamyltranspeptidase
activity (γGT). Histopathology, constitutional
and viral factors, or alcohol consumption may be involved in this effect, but
little information is available. The aim of our study was to assess factors
affecting γGT activity in patient with chronic
hepatitis C by carefully selecting patients with no present or past history of
alcohol intake.
We selected 63 consecutive patients with biopsy proven
chronic hepatitis C and no history of alcohol consumption. We measured
pretreatment anthropometric parameters and insuline
resistance (HOMA IR) in addition to conventional virological and serological
liver tests. Forty patients were also tested for small intestinal bacterial
overgrowth using glucose H2 breath test. Liver histology was classified
according to Knodell and hepatic steatosis according to Brunt. All patients
were treated with PEG-interferon alfa 2-b (1.5 μg/kg/weekly)
plus ribavirin (800 to 1200 mg/day according to body weight).
Thirty-eight patients had pretreatment γGT > 1 the upper limit of normal, and 25 had
values within the normal range. There was no difference in pretreatment viral
load and genotype distribution among the 2 groups. Peptide-C (mean + SD: 2.98 ±
1.66 ng/mL vs 2.04 ± 0.90 ng/mL, p=0.0175), insuline
resistance (2.83 ± 1.9 vs 1.79 ± 1.12, p=0.023) and
hepatic steatosis score (0.78 ± 0.5 vs 0.22 ± 0.43,
p=0.001) were significantly higher in patients with high than in those with
normal γGT. No patient tested positive at
glucose H2 breath test Insuline resistance (r=0.467,
p<001), hepatic staging (r=0.313, p <0.05) and steatosis (r=0.399,
p<0.007) were significantly related (Pearson correlation) to serum γGT. Hepatic steatosis was the only parameter
independently related to serum GGT (r=0.510, p <0.007) at multiple
regression analysis.
In conclusion, a substantial proportion of patients
with chronic hepatitis C that are not alcohol consumers have serum γGT activity above the upper limit of normal. This
phenomenon is independent of constitutional or virological characteristics and
is associated with hepatic steatosis at histopathology, suggesting that
increased serum GGT activity may represent a surrogate marker of hepatic non
alcoholic steatosis.
Abstract S1049 – Sinusoidal
Lymphocytosis as a Marker for
Cryoglobulinemia in Hepatitis C Liver Biopsies
S. Carmack; W. Ahrens; P. Ravichandran; P. Hui; M. Robert; T. Taddei; P. Mistry; D. Jain
Background:
Cryoglobulinemia (CryoG) is
commonly seen with hepatitis C virus (HCV) and is associated with a higher grade
of fibrosis, increased incidence of low-grade non-Hodgkin lymphoma, and poorer
response to therapy. The development of CryoG may be
a marker of chronic antigenic stimulation by HCV that in some cases leads to clonal B-cell proliferation and lymphoma. Currently no
histological findings in liver biopsy are known to correlate with the presence
of CryoG in HCV infected patients. We have
anecdotally noted prominent sinusoidal lymphocytosis
in CryoG liver biopsies. The goal of this study is to
determine whether this could be used as a marker of CryoG
in liver biopsies from chronic HCV patients.
Design:
10 chronic HCV patients with CryoG
who underwent biopsy from 1998-2005 were identified from the liver clinic
database. 10 HCV CryoG-negative cases matched for age
and stage of fibrosis were included as controls. Histological features
(sinusoidal lymphocytes, inflammatory activity, acidophil bodies, fibrosis
stage), and clinical and laboratory data (SPEP, LFT's,
HCV viral load, EBV status, treatment), were evaluated. Formalin-fixed paraffin
embedded sections were stained for CD3, CD20 and CD68. Sinusoidal lymphocytes
were counted in 5 HPF on H&E, CD3 and CD20 immunostains.
CD68+ Kuppfer cells were counted in a similar
fashion.
Results:
The mean and standard deviation (SD) of fibrosis
stage, inflammatory grade, and lymphocyte/Kuppfer
cell counts are shown in the table. CryoG-positive
cases were significantly correlated with increased sinusoidal T-cell lymphocytosis (P=0.028) as compared to CryoG-negative
cases. There were no differences in the two groups with other histological
parameters.
Conclusion:
CryoG-positive liver biopsies
show a prominent sinusoidal T-cell lymphocytosis
compared to CryoG-negative biopsies. These T-cells
probably imply increased antigenic stimulation and may play a role in the
pathogenesis of CryoG. However, this needs further
investigation. Evaluation of this feature on the diagnostic work-up of liver
biopsies may have important implications with regard to further work-up,
treatment, and follow-up of these patients.
|
|
Stage |
Grade |
H&E Lymphocytes |
CD3+ cells |
CD20+ cells |
CD68+ cells |
|
CryoG + (mean +/- SD) |
2.4 +/- 1.2 |
1.8 +/- 0.9 |
247 +/- 183 |
318 +/- 244 |
42 +/- 54 |
239 +/- 46 |
|
CryoG- (mean +/- SD) |
2.4 +/- 0.5 |
2.1 +/- 0.7 |
180 +/- 42 |
113 +/- 50 |
15 +/- 7 |
220 +/- 51 |
Abstract
S1050 – Liver fibrosis and necroinflammatory activity
in chronic hepatitis C patients with persistently normal aminotransferases
A. M. Loaeza; F. Sanchez-Avila;
J. Gallegos-Orozco; E. Oviedo; M. Weimersheimer; M.
Sanchez; A. Meixueiro; J. Garcia; G.
Introduction:
Liver fibrosis (LF) progression in chronic hepatitis C
(CHC) patients is considered to be linear and accelerated at advanced stages.
Natural history of liver fibrosis in patients with normal ALT levels is
uncertain, in liver biopsy minimal inflammation and LF are often found, so a
less aggressive form of disease has been speculated, nonetheless advanced lessions such as bridging fibrosis and cirrhosis have been
reported.
Aim:
To compare LF stage and degree of necroinflammatory
activity (IA) in CHC patients with normal ALT versus CHC patients with elevated
ALT.
Method:
CHC treatment-naive patients with a liver biopsy and
known duration of infection were included. CHC with normal ALT was defined as
HCV-RNA detectable in serum and at least 3 ALT values in the normal range
within a 6 months period. All liver biopsies were evaluated according to
METAVIR score by one blinded pathologist. LF, IA and LF progression were compared
between both groups. Advanced LF was defined as a METAVIR >= F2.
Results:
158 patients were included, mean age 50 +/- 12
years-old, 101 (64%) were female. 96 (61%) had elevated ALT and 62 (39%) had
normal ALT, the mean ALT value in both groups was 139 UI/L and 47.8 IU/L (P
< 0.0001) respectively. The LF progression rate was 0.102 and 0.125 METAVIR
points/year (P=0.352), with a mean duration of infection of 22.4 vs 26 years (P=0.07) in patients with normal and elevated
ALT respectively. 31 patients with normal ALT (50%) and 58 patients with
elevated ALT (60.4%) had advanced LF (P=0.25). Differences in LF and IA between
groups are shown in the table.There was an
association between elevated ALT levels and the presence of A3 (OR 4.6, 95% CI,
1.02-21.5; p<0.05) and F4 (OR: 5.9, 95% CI, 2.9-12.1; p<0.001),
conversely normal ALT levels were associated with F0 (OR:0.4, 95% CI,
0.17–0.94; p < 0.05).
Conclusions.
In the studied population, severe IA and cirrhosis
were more frequent in patients with elevated ALT. Although the absence of LF
was more frequent in patients with normal ALT, half of them showed significant
fibrosis. In the abscense of validated non-invasive
LF markers in patients with persistently normal ALT, a liver biopsy should be
considered, specially in those with a long term infection.
|
Fibrosis METAVIR |
F0 (n=28) |
F1 (n=41) |
F2 (n=23) |
F3 (n=17) |
F4 (n=48) |
|
Normal ALT n (%) |
16 (26) |
15 (24) |
10 (16) |
9(15) |
12 (19) |
|
Elevated ALT n (%) |
12 (12.5) |
26 (27) |
13 (13.5) |
8 (8.5) |
36 (37.5) |
|
P |
<0.05 |
0.7 |
0.5 |
0.2 |
<0.001 |
Necroinflammation
|
Necroinflammatory activity METAVIR |
A0 (n=17) |
A1 (n=81) |
A2 (n=45) |
A3 (n=15) |
- |
|
Normal ALT n (%) |
10 (16) |
34 (55) |
16 (26) |
2 (3) |
- |
|
Elevated ALT n (%) |
7 (7) |
47 (49) |
29 (30) |
13 (14) |
- |
|
P |
0.08 |
0.5 |
0.5 |
<0.05 |
- |
Abstract S1051 – High accuracy pre-treatment prediction of
Early Viral Response to combined pegIFN/ribavirin therapy
in HCV-infected patients by a novel method of gene expression analysis: a
preliminary study.
J. Alsobrook; P. Hraber; C. Harris; L. Davis; P.
Doherty; B. Griffith; T. Williams; S. Arora
Background
Current predictors of Sustained Viral Response (SVR)
to HCV therapy have limited power. Accurate prediction of treatment response
prior to therapy would have great clinical utility. Exagen’s
goal is to discover small sets of genomic biomarkers for prognostic testing.
This pilot study was designed to discover a small suite of genes whose combined
expression pattern distinguishes patients with a 12-week Early Viral Response
(EVR) from non-responders.
Patients
Protocols were IRB approved; informed consent was
obtained from all patients prior to enrollment. Clinical data and blood samples
were collected from 47 HCV-infected patients.
Analysis
Total mRNAs were isolated, and cDNAs
were prepared, from pre-treatment blood samples and a reference sample derived
from a commercial source of normal tissues. All cDNAs
were assayed with a custom microarray representing
24,000 human genes. Array data were analyzed with Exagen’s
proprietary software which uses an empirical, data-driven computational
methodology with no prior assumptions about biological relationships, whereby
the predictive classification accuracy of gene combinations are evaluated
directly without regard to (or assessment of) the accuracy of individual genes.
The significance of any resultant combinatorial classifier is evaluated by an
iterative random permutation process. Patients were classified as responder or
non-responder by EVR status (undetectable viral RNA / zero viral titer or
detectable viral titer, respectively). Of the 47 cases enrolled, 3 had
incomplete data. The remaining 44 cases were randomly assigned to a training
set and a test set. The training set contained 25 responders & 8
non-responders for use in a classifier search, and the test set contained 8
responders & 3 non-responders for use in classifier assessment.
Results
Multiple classifier sets derived from pre-treatment
blood samples gave high overall accuracy for predicting EVR; one gene appeared
consistently among the best classifiers. A 2-gene classifier achieved an
overall 97% accuracy in the training set (32 out of 33 correctly classified),
and an overall 81.8% accuracy in the test set (9 out of 11 correctly
classified). This successful pilot study for pre-treatment prediction of HCV
EVR suggests that our method may be successfully applied to HCV SVR,
particularly in light of the high negative predictive value of EVR for SVR
outcome.
Conclusion
This successful pilot study for pre-treatment
prediction of HCV Early Virological Response will be extended in a larger
clinical sample. The same discovery
method may also be successfully applied to HCV Sustained Viral Response,
particularly in light of the high negative predictive value of EVR for SVR.
|
|
|
Genotype 1 |
Genotype 2 |
Genotype 3 |
|
EVR |
+ |
20 |
7 |
6 |
|
EVR |
- |
11 |
0 |
0 |
|
|
Training EVR |
Test EVR |
||||
|
Classifier Prediction |
|
+ |
- |
+ |
- |
|
|
+ |
24 |
0 |
7 |
1 |
|
|
|
- |
1 |
8 |
1 |
2 |
|
|
N. Dharel; N. Kato; R. Muroyama; M.
Moriyama; R. Shao; T. Kawabe;
M. Omata
Background:
Hepatitis C virus (HCV) infection remains a major
cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC)
worldwide. Over 80% of all HCC in
Patients and Methods:
We genotyped the SNP309 at the MDM2 promoter in
435 Japanese patients with chronic HCV infection including 187 patients with
HCC, as well as 48 healthy volunteers, using a fluorogenic
polymerase chain reaction (TaqMan SNP genotyping
assay). The result of the SNP assays were also verified by direct sequencing of
some randomly selected samples.
Results:
The genotype distribution of SNP309 among Japanese
population including 435 patients with chronic hepatitis C and 48 healthy
controls were as follows: (T/T - 22%, T/G - 51% and G/G - 27%) and were
different from the original report in Caucasian population (48%, 40% and 12%,
respectively) (Bond et al. Cell 2004). Among the chronic hepatitis C patients,
the proportion of G/G genotype of the SNP309 in 187 patients with HCC (33%) was
significantly higher than in the 248 patients without HCC (23%), with an odds
ratio of 2.28 (95% confidence interval 1.30 – 3.98). A multivariate analysis
revealed that MDM2 SNP309 (G/G vs. T/T), age over 60, male gender,
presence of cirrhosis, serum alpha-fetoprotein >20 μg/L,
and serum albumin <3.2 gm/dL were independently
associated with the HCC development at odds ratio of 2.27, 2.46, 3.08, 4.15,
4.87, and 6.33, respectively.
Conclusions: MDM2 promoter
SNP309 is associated with development of HCC in Japanese patients with chronic
hepatitis C. The G allele of MDM2 SNP309 could serve as an important
genetic marker for the risk of HCC among patients with chronic hepatitis C.
R.
Sirli;
I. Sporea; A. Popescu; M. Danila; M. Cornianu
Aim:
The aim of this paper is to compare the severity of
hepatic lesions evaluated by means of liver biopsy (LB) at the moment of diagnosis,
in patients with Chronic B viral hepatitis vs. patients with Chronic C viral
hepatitis.
Material and method:
We evaluated 846 consecutive patients diagnosed in our
department with chronic B and C viral hepatitis. In all these patients we
performed LB that was evaluated by means of Knodell score. We compared the
demographic data of the two groups, as well as the severity of hepatic lesions
(histology activity index – HAI, and the fibrosis score).
Results:
From the total of 846 patients, 247 (29.2%) had
chronic B hepatitis and 599 (70.8%) chronic C hepatitis. The mean age at
diagnosis was 39.9+/-12.2 in HBV patients and 47.7 +/-10.7 in HCV patients
(p<0.0001). From the 247 HBV patients, 39.7% (98) were female, while from
the 599 HCV patients, 59.3% (355) were female (p<0.0001).
Regarding the severity of liver damage on LB, the mean
HAI score was 7.14+/-3.35 in HBV patients and 8.11 +/- 2.86 in HCV patients
(p<0.0001). The mean fibrosis score was 1.10+/-1.15 in HBV patients and 1.3
+/- 1.18 in HCV patients (p=0.02 S).
In HBV patients there were no statistically
significant differences between men and women regarding the severity of hepatic
lesions: mean HAI score 7.13 +/- 3.2 in women and 7.14 +/- 3.4 in men (p=0.93);
mean fibrosis score 1.09+/-0.12 in women and 1.12+/-0.09 in men (p=0.66).
Also, in HCV patients there were no statistically
significant differences between men and women regarding the severity of hepatic
lesions: mean HAI score 8.06 +/- 2.9 in women and 8.13 +/- 2.72 in men
(p=0.68); mean fibrosis score 1.27+/-1.16 in women and 1.34+/-0.22 in men
(p=0.56).
Conclusions:
1. In our group chronic C viral hepatitis was 2.5
times more frequent than B chronic hepatitis (599 vs. 247 cases).
2. The age at diagnosis was significantly lower in HBV
patients as compared to HCV patients (39.9 vs. 47.7, p<0.0001).
3. C chronic hepatitis was significantly more frequent
in women than in men (female-male ratio = 1.45:1), as compared to B chronic
hepatitis (female-male ratio=1:1.52) (p<0.0001)
4. There were no statistically significant differences
between men and women regarding the severity of hepatic lesions, in both HBV
and HCV groups of patients.
5. The hepatic lesions were significantly more severe
in patients with chronic C hepatitis than in those with chronic B hepatitis,
regarding both the mean HAI score (8.11 vs. 7.14, p<0.0001), and the mean
fibrosis score (1.3 vs. 1.1, p=0.02).
Abstract
S1055 – Non-invasive Biomarkers
of Liver Fibrosis in Hemophilia Patients
with Hepatitis C: Can You Avoid Liver Biopsy?
Y. Maor; D. Bashari; G. Kenet; A. Lubetsky; J. Luboshitz ; J. M. Schapiro ; G. Penaranda ; S. Bar-Meir; U. Martinowitz; P. Halfon
Introduction:
Liver biopsy remains the gold standard for the
evaluation of fibrosis despite its risks and limitations, especially in
hemophilia patients. Recently, non-invasive biomarkers were used to assess
histological features. The most thoroughly evaluated biomarker is the Fibrotest (FT) (AUROC 0.80 for fibrosis stages F2F3F4 vs.
F0F1).
Aim:
To assess liver fibrosis in hemophilia patients with
HCV using non-invasive biomarkers without liver biopsy. Methods: One-hundred
and thirty two hemophilia patients (124 males, mean age 39 ± 14 years) with
anti-HCV antibodies were evaluated. These patients were stratified into several
groups: patients with features of advanced liver disease- 7, persistently HCV
RNA-negative- 21, persistently normal LFT's- 24,
HCV/HIV co-infected- 27. The following biomarkers of fibrosis were used: FT,
AST-to-platelet ratio index (APRI), Forns index,
age-platelet index and hyaluronic acid. The obtained scores were correlated
with the clinical features of the patients.
Results:
Estimated by the FT, the distribution of the stage of
fibrosis in the 132 patients was: F0F1=65% (86/132), F2=5% (7/132), F3=13%
(17/132) and F4=17% (22/132). Using FT, all patients with clinical suspicion of
advanced liver disease were classified as F3F4, whereas patients with persistently
HCV RNA-negative were all classified as F0F1. Twenty-one percent (5/24) of the
patients with persistently normal LFT's had fibrosis
stage F3F4. The proportion of F3F4 among HCV/HIV co-infected patients was
significantly higher than among HCV mono-infected (52% vs. 33%; p=0.05).
Concordance of 3 or more biomarkers was present in 43% (57/132) of the
patients. Liver biopsy could be avoided in 70% of the patients using a
practical assumption that if FT is in concordance with APRI and/or Forns than there is a concordance with liver biopsy. The
concordance rate for patients with presumably advanced or minimal liver disease
was excellent (100% and 95%, respectively).
Conclusions:
In our hemophilia patients infected with HCV, FT
identified correctly advanced or minimal liver disease. Discordance among the
various biomarkers of fibrosis was considerate; nevertheless, practical
combination of FT, APRI, and Forns may predict stage
of fibrosis with accuracy, avoiding liver biopsy in 70% of the patients.
Abstract S1056
– Steatosis
associated with more severe fibrosis in
in chronic hepatitis C.
K. Corey;
A. K. Bhan; R. T. Chung
Background and Aims
Recent work has suggested that steatosis contributes
to more advanced fibrosis in patients with chronic hepatitis C (CHC). The
etiology of this steatosis varies by genotype. In genotype 3 steatosis the
hepatitis C virus (HCV) is believed to initiate steatosis while in genotype 1
the steatosis is likely metabolic in origin. These etiologies of steatosis may
have important implications for adjunctive therapy in HCV. We sought to assess
the relationship between steatosis and fibrosis in a cohort of patients with
CHC who underwent liver biopsy and further establish the relationship between
fibrosis and steatosis when limited to genotype 1.
Methods
A retrospective chart review of 223 patients with CHC
and liver biopsy was undertaken to assess relationship between steatosis and
fibrosis. HCV RNA, genotype, AST, ALT, presence of diabetes mellitus,
hypertension and hyperlipidemia were recorded.
Biopsies were analyzed by a single pathologist (AKB)
and graded for necroinflammatory activity and
fibrosis staging according to Ishak et al. as well as Brunt steatosis score.
Steatosis was scored on a scale of 0-4, with 0 = no steatosis, 1= <5%,
2=5-33%, 3=34-66% and 4=>66% of hepatocytes with steatosis.
Results
Steatosis was observed in 66% of CHC patients in this
group. Fibrosis was found on liver biopsy in 77% of patients. Mean fibrosis
score was 2.51+/- 1.47 and the mean steatosis score 0.99 +/-0.9. Twenty-seven
percent and 66% of genotype 1 pts had grade 2+ and 1+ steatosis, respectively.
Thirty percent and 78% of genotype 3 patients had grade 2+ and 1+ steatosis,
respectively. While an absolute correlation between steatosis score and
fibrosis stage was not observed, when fibrosis was dichotomized to low fibrosis
(stage 0-2) and severe fibrosis (grade 3-6) a significant relationship with
steatosis was seen. (Pearson Chi2 = 11.9, p = 0.008). A significant
relationship between steatosis and fibrosis was also observed when the data was
confined to genotype 1 (p=0.05).
Conclusion
This finding that increased steatosis is associated
with worsening fibrosis suggests a possible role for steatosis in the
acceleration of liver disease in HCV patients, especially in genotype 1 patients.
Efforts to control steatosis may therefore have an important role in halting
HCV liver disease progression, particularly in persons who are nonresponders to
antiviral therapy.