Advances in Digestive Medicine (2015) 2, 102e107

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ORIGINAL ARTICLE

Serum hepatitis B surface antigen level

might predict cirrhosis and hepatocellular
carcinoma in older patients with chronic
hepatitis B
Pei-Lun Lee a, Jyh-Jou Chen a,*, Hung-Da Tung a,
Chun-Ta Cheng a, Tang-Wei Chuang a, Szu-Jen Wang a,
Hsien-Cheng Wu b
a
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi-Mei Medical
Center, Liouying, Tainan, Taiwan
b
Department of Clinical Pathology, Chi-Mei Medical Center, Liouying, Tainan, Taiwan

Received 17 January 2014; accepted 24 June 2014

Available online 6 March 2015

KEYWORDS
Chronic hepatitis B;
Older patients;
Serum hepatitis B
surface antigen level

Summary Background and aim: Distinguishing inactive hepatitis B surface antigen (HBsAg)
carriers from hepatitis B e antigen-negative hepatitis remains difficult but is important
because patients with active hepatitis may develop severe complications. Long-term followup data with stringent criteria are required for the identification of inactive HBsAg carriers.
A single serum HBsAg level may be used to solve this difficult diagnostic issue; however, very
few studies on its application in older patients have been published. This study was designed to
evaluate the clinical significance of a single serum HBsAg level in older patients with chronic
hepatitis B (CHB).
Materials and methods: From January 2012 to December 2012, the clinical manifestations of
1749 HBsAg-positive patients were analyzed including 412 patients aged  60 years (mean
age at enrollment, 68.6  6.9 years; range, 60e90 years; 262 males and 150 females). We
investigated the possibility of using a single serum HBsAg level to predict cirrhosis and hepatocellular carcinoma (HCC) in older patients with CHB.
Results: Of the 1749 HBsAg-positive patients, those aged  60 years tended to have lower
serum HBsAg levels than the younger patients. In fact, all patients aged  60 years had a serum

* Corresponding author. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi-Mei Medical Center, Liouying,
Number 201, Taikan, Liouying, Tainan 736, Taiwan.
E-mail address: jjchen@mail.chimei.org.tw (J.-J. Chen).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://
creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any
medium, provided the original work is properly cited.
http://dx.doi.org/10.1016/j.aidm.2014.06.003
2351-9797/Copyright 2015, The Gastroenterological Society of Taiwan, The Digestive Endoscopy Society of Taiwan and Taiwan Association
for the Study of the Liver. Published by Elsevier Taiwan LLC. All rights reserved.

Serum HBsAg level might predict cirrhosis and HCC

103

HBsAg level  10,000 IU/mL. Of the 412 patients aged  60 years, 122 (29.6%) had cirrhosis and
59 (14.3%) developed HCC. When an HBsAg-titer < 100 IU/mL was used to examine severe clinical outcomes (cirrhosis or HCC), the sensitivity, specificity, positive predictive value, and
negative predictive value for being free of liver cirrhosis and HCC were 49.3% and 95.2%,
19.7% and 28.8%, 85.6% and 95.2%, and 40.0% and 71.2%, respectively.
Conclusion: A single serum HBsAg level < 100 IU/mL might predict favorable clinical results in
older patients with late-stage CHB virus infection.
Copyright 2015, The Gastroenterological Society of Taiwan, The Digestive Endoscopy Society
of Taiwan and Taiwan Association for the Study of the Liver. Published by Elsevier Taiwan LLC.
All rights reserved.

Introduction
Chronic hepatitis B (CHB) remains a challenging health
problem in Taiwan. More than 3 million people in Taiwan
are chronically infected with hepatitis B virus (HBV) and are
at high risk of developing hepatic decompensation,
cirrhosis, and hepatocellular carcinoma (HCC) [1]. Patients
who acquire the infection during the perinatal period or
infancy period have three clinical phases, namely, immune
tolerant, immune clearance, and inactive residual [2].
However, during the inactive residual phase, CHB reactivation may occur in some patients, which progresses to
the fourth reactivation phase (otherwise called the variant
phase of immune clearance) [1,3e5]. Patients with reactivation may develop cirrhosis and HCC. Taiwanese studies
found a reactivation rate of 2e3% per year and a cumulative rate of 20e25% after 15 years of follow up [4e6].
With stringent criteria including close monitoring of
alanine transaminase (ALT) and HBV-DNA levels to avoid
misclassification, inactive hepatitis B surface antigen
(HBsAg) carrier had excellent outcome [7]. To define a true
inactive HBsAg carrier, patients should be followed up
regularly for a long period with persistently normal ALT
(PNALT) levels and persistently low HBV-DNA levels [8e10].
However, ALT abnormalities may occur due to cofactors
(such as alcohol or drugs) rather than HBV reactivation
[8,10,11]. The serum HBV-DNA level, which is reflective of
HBV replication, is a key factor of disease progression [12].
Stringent monitoring of HBV replication levels in addition to
ALT monitoring is more effective in distinguishing between
active and inactive HBsAg carriers [7]. However, there are
some barriers to monitoring HBV-DNA levels during followup evaluations in clinical practice in Taiwan.
The serum HBsAg level has served as a quantitative
diagnostic marker for HBV infection and is easy to measure.
The relationship between intrahepatic markers of HBV
infection (covalently closed circular DNA and integrated
HBV DNA) and serum HBsAg levels has been considered a
marker of active hepatitis and may predict clinical outcomes [13e17]. Recent studies reported that a single-point
evaluation of serum HBV-DNA (< 2000 IU/mL) and HBsAg (<
1000 IU/mL) levels provides complementary information to
distinguish between active and inactive HBV genotype D
carriers, and the use of a single serum HBsAg level may
reflect the clinical stage [18,19].
Older HBsAg-positive patients who acquired HBV infection
during the perinatal or childhood period represented either

late-stage inactive HBsAg carriers or those with CHB reactivation. Patients with low-serum HBsAg levels in the later
stage of CHB infection may be long-term inactive HBsAg
carriers and have a favorable outcome. We conducted this
study to evaluate the clinical significance of a single serum
HBsAg level in predicting favorable clinical outcomes in older
patients who live in areas highly endemic for CHB.

Materials and methods

Study populations
Liouying is located in the northern part of Tainan County,
which is an area in southern Taiwan with hyperendemic HBV
infection [20]. The Chi-Mei Medical Center in Liouying is a
tertiary hospital that receives patient referrals for antiviral
therapy for CHB. The majority of its patients live in the
northern part of Tainan County.
This study was approved by the Ethics Committee of ChiMei Medical Center. Between January 2012 and December
2012, 1749 HBsAg-positive patients (serum HBsAg level 
0.05 IU/mL) were followed up at our hospital. The serum
HBsAg levels of the patients with a history of hepatitis B
confirmed by a qualitative test for HBsAg positivity before
January 1, 2012, were measured during the study period. In
addition, patients who were suspected to have hepatitis or
underwent hepatitis B screening for any reason during the
study period underwent evaluation of serum HBsAg levels.
Table 1 presents the serum HBsAg levels of patients in
different age groups. Patients without available antihepatitis C virus (anti-HCV) data, those aged  60 years, or
those with both hepatitis B and C virus infections were
excluded. Finally, a total of 412 patients were enrolled and
their clinical manifestations were analyzed. Patients ages
and their clinical manifestations were retrieved from
medical records for analysis. Because acute hepatitis B is
rare in older individuals in this highly endemic area, CHB
was diagnosed if a single serum HBsAg test result was positive. Serum HBsAg levels were tested for abnormal ALT
level or hepatitis history in 318 patients, before chemotherapy in 74 patients, and for routine admission in 20 patients. None of the patients received antiviral therapy
before their serum HBsAg levels were tested.
The definition of PNALT was that all ALT data that had
been checked in our hospital were within normal limits
because the examination intervals differed among inactive

104

P.-L. Lee et al.

Table 1

Proportion of the serum HBsAg level in patients with chronic hepatitis B by different age subgroups.

Age

<20 y %

20e29 y %

30e39 y %

40e49 y %

50e59 y %

60e69 y %

70e79 y %

>80 y %

Total

M:F
<1 L
1e2 L
2e3 L
3e4 L
4e5 L
5e6 L

0.67
1
0
1
1
2
0
5

0.86
6
10
6
25
15
3
65

1.42
42
30
72
144
48
8
344

1.73
54
64
84
143
27
2
374

1.67
85
78
137
140
10
1
451

1.71
53
61
96
77
6
0
293

1.46
46
41
49
39
0
0
175

1.63
10
7
15
10
0
0
42

297
291
460
579
108
14
1749

(20)
(0)
(20)
(20)
(40)
(0)

(9)
(15)
(9)
(38)
(23)
(5)

(12)
(9)
(21)
(42)
(14)
(2)

(14)
(17)
(22)
(38)
(7)
(1)

(19)
(17)
(30)
(31)
(2)
(0)

(18)
(21)
(33)
(26)
(2)
(0)

(26)
(23)
(28)
(22)
(0)
(0)

(24)
(17)
(36)
(24)
(0)
(0)

HBsAg Z hepatitis B surface antigen.

carriers, patients with active hepatitis, and patients with

cirrhosis. We grouped patients into cirrhotic and noncirrhotic groups, which included inactive carriers and patients with active hepatitis because it was difficult to
identify inactive carriers in this cross-sectional study. The
severe clinical outcomes included patients who had HCC
and/or cirrhosis. Cirrhosis was diagnosed using ultrasonographic features and procedures based on the criteria reported by Lin et al [21]. HCC was diagnosed by two of the
three following imaging methods: ultrasonography,
computed tomography, and magnetic resonance imaging
with typical HCC imaging.

Laboratory tests
Serological and biochemical examinations
The level of alanine aminotransferase (normal upper limit,
50 IU/L) was measured on a multichannel autoanalyzer
(Hitachi-7600; Tokyo, Japan). HBsAg and second-generation
HCV antibody were detected using commercially available
enzyme-linked immunosorbent assay kits (Abbott, North
Chicago, IL, USA). HBsAg was monitored using chemiluminescent microparticle immunoassay (ARCHITECT HBsAg,
Abbott Laboratories, Barceloneta, Puerto Rico; quantitative limit between 0.05 and 250 IU/mL). The samples were
diluted to maintain titer > 250 IU/mL when necessary. The
HBV-DNA levels were investigated in the serum samples
using the real-time polymerase chain reaction technique
(COBAS AmpliPrep and TaqMan HBV Test; Roche, Mannheim, Germany; quantitative limit between 12 and
110,000,000 IU/mL).

Statistical analyses
Discrete variables were expressed as numbers (n) and frequency (%), and statistically tested using the Chi-square
test or Fisher exact test. Continuous variables were
expressed as mean  standard deviation and were statistically tested by the two-tailed Student t test. All p values
< 0.05 were considered statistically significant.

Results
A total of 412 patients (mean age at enrollment, 68.6  6.9
years; range, 60e90 years; 262 males and 150 females)

were enrolled in this study. Patients aged  60 years tended

to have lower serum HBsAg levels (Table 1), and none had a
serum HBsAg > 10,000 IU/mL.
Among the patients participating in our study, 322
(78.2%) patients were screened for hepatitis B e antigen
(HBeAg) and 307 (95.0%) were HBeAg negative. Of the
HBeAg-positive patients, 12 of 15 (80%) patients were aged
60e69 years (Table 2).
A total of 245 (59.5%) patients had a serum HBsAg level >
100 IU/mL, including a subgroup of 113 (27.4%) patients
whose HBsAg levels were >1000 IU/mL. The proportions of
patients with the HBsAg level > 100 IU/mL were evenly
distributed among the age groups of 60 years, 70 years, and
80 years (Table 2). A total of 143 (34.7%) patients had
PNALT and there were no significant differences among
patients in the different age groups (Table 2).
Severe clinical outcomes were found in 122 (29.6%) patients with cirrhosis and in 59 (14.3%) patients who developed HCC. Severe clinical outcomes were evenly
distributed between patients in the different age groups.
However, the proportion of patients with cirrhosis
increased from 26.8% in the 7th decade to 36.1% in the 9th
decade of life (p > 0.05; Table 2). Twenty-three percent
(98/412) of patients had cirrhosis and an HBsAg level >
100 IU/mL, whereas 5.8% (24/412) had cirrhosis and an
HBsAg level < 100 IU/mL (p < 0.0001). When a serum HBsAg
level < 100 IU/mL was used to predict whether patients
were free of liver cirrhosis, the sensitivity, specificity,
positive predictive value (PPV), and negative predictive
value (NPV) were 49.3%, 19.7%, 85.6%, and 40.0%, respectively. When this criterion was used to predict whether
patients were free from HCC, the sensitivity, specificity,
PPV, and NPV were 95.2%, 28.8%, 95.2%, and 71.2%,
respectively (Table 3).
When a serum HBsAg level > 100 IU/mL was used to
predict liver cirrhosis, the sensitivity and NPV were 80.3%
and 85.6%, respectively. When this criterion was used to
predict HCC, the sensitivity, specificity, PPV, and NPV were
71.2%, 4.8%, 71.2%, and 95.2%, respectively (Table 3).
A total of 216 (52.4%) patients underwent HBV-DNA level
examination within 1 month of the HBsAg level assessment.
Of these patients, 66.7% had an HBV-DNA level > 2000 IU/
mL (Table 2). We did not analyze the predictive value of the
serum HBsAg level combined with the HBV-DNA level,
because the latter was not available for half of the enrolled
patients.

Serum HBsAg level might predict cirrhosis and HCC

Table 2

105

Clinical manifestations in patients with chronic hepatitis B by different age subgroups.

No.
Follow up (mo)
M:F
Age (y)
HBsAg (IU/mL)
HBsAg > 100 IU/mL
HBsAg > 1000 IU/mL
HBeAg (n)
HBeAg (e)
HBV DNA (log)
>2000 IU/mL
ALT (IU/mL)
ALT > 50
PNALT
LC
LC and HBsAg > 100 IU/mL
LC and HBsAg < 100 IU/mL
HCC
HCC and HBsAg > 100 IU/mL
HCC and HBsAg < 100 IU/mL

>60 y

60e69 y

70e79 y

>80 y

412
82.71  75.43
1.7
68.6  6.9
1153.2  4256.9
245 (59.5)
113 (27.4)
322 (78.2)
307 (95.3)
7.25  8.26
144/216 (66.7)
105.4  252.7
154 (37.4)
143 (34.7)
122 (29.6)
98 (23.8)a
24 (5.8)a
59 (14.3)
42 (10.2)
17 (4.1)

250
82.41  55.74
1.7
64.0  2.8
1435.3  5340.1
156 (62.4)
74 (29.6)
206 (82.4)
194 (90.7)
6.81  7.45
104/147 (70.7)
117.6  287.5
97 (38.8)
80 (32.0)
67 (26.8)

126
83.45  109.63
1.8
73.5  2.6
752.8  1476.4
66 (52.4)
30 (23.8)
93 (73.8)
91 (97.8)
6.65  7.39
27/53 (50.9)
64.5  119.0
40 (31.7)
50 (39.7)
42 (33.3)

36
82.14  42.13
1.6
83.8  2.9
595.1  814.1
23 (63.9)
9 (25.0)
23 (63.9)
22 (95.7)
8.21  8.81
13/16 (81.3)
163.7  317.6
17 (47.2)
13 (36.1)
13 (36.1)

>0.05
>0.05
>0.05
>0.05
>0.05
>0.05
>0.05

30 (12.0)

24 (19.0)

5 (13.9)

>0.05

p
>0.05

0.05
>0.05
>0.05

ALT Z alanine transaminase; HBeAg Z hepatitis B e antigen; HBsAg Z hepatitis B surface antigen; HBV Z hepatitis B virus;
HCC Z hepatocellular carcinoma; LC Z liver cirrhosis; PNALT Z persistently normal alanine transaminase level.
a
LC and HBsAg > 100 IU/mL versus LC and HBsAg < 100 IU/mL: p < 0.001; HCC and HBsAg > 100 IU/mL versus HCC and HBsAg < 100 IU/
mL: p < 0.05.

Discussion
In Asia, HBeAg seroconversion tends to occur in patients
aged 30e35 years, and most patients (90%) develop it
before the age of 40 years [22e25]. In our study, patients
enrolled were all aged  60 years and 90% of them were
HBeAg negative, which supported this observation. Among
patients developing HBeAg seroconversion before the age
of 30 years, only a very low portion will experience relapse.
However, a higher proportion of patients who experience
HBeAg seroconversion after the age of 40 years will experience relapse [26,27]. A Taiwanese study reported that
20e25% of patients developed recurrent active hepatitis
during a 15-year follow-up period and these patients tended to develop cirrhosis or HCC [4,28e32]. Our study, which
included patients in the later stage of CHB, found that
29.6% of patients had cirrhosis, which supported previous
results.
Table 3

Cutoff values for predicting freedom from liver cirrhosis or hepatocellular carcinoma.

Liver cirrhosis

HCC

One stringent criterion used to identify patients who are

inactive HBsAg carriers resulted in the identification of only
a limited number of patients in longitudinal cohort studies
[7]. In our study, 30e40% of the patients had PNALT, and
ALT level fluctuation may be caused by cofactors and do not
necessarily indicate CHB severity.
HBV replication that is reflected by the serum HBV-DNA
level is the key factor of disease progression [12]. According
to the National Institutes of Health and the European Association for the Study of the Liver guidelines, the differentiation between inactive and active phases of HBeAgnegative CHB is based on an HBV-DNA cutoff level of
2000 IU/mL. These criteria, however, led to some controversial results [14,33,34]. Thus, stringent monitoring of HBV
replication levels in addition to ALT levels to avoid
misclassification of the HBV infection profile caused by
HBV-DNA level fluctuations during cross-sectional evaluation was recommended [7,31]. Patients with an HBV DNA >

Sensitivity
Specificity
PPV
NPV
Sensitivity
Specificity
PPV
NPV

HBsAg < 100 IU/mL (%)

HBsAg > 100 IU/mL (%)

HBsAg > 1000 IU/mL (%)

49.3
19.7
85.6
40.0
95.2
28.8
95.2
71.2

80.3
50.7
40.0
85.6
71.2
4.8
71.2
95.2

47.5
64.5
23.7
61.7
45.8
9.1
45.8
90.9

HBsAg Z hepatitis B surface antigen; HCC Z hepatocellular carcinoma; NPV Z negative predictive value; PPV Z positive predictive
value.

106
2000 IU/mL had a predisposition for hepatic flares [31,32].
However, patients with PNALT may have HBV-DNA levels >
20,000 IU/mL, and this finding supports the recommendation of monitoring the HBV-DNA level in addition to the ALT
levels to define the inactive HBsAg carrier state [4,5,32]. All
of these studies demonstrated the limitation of using a
single serum HBV-DNA level or ALT monitoring to predict
inactive carrier status.
Studies have shown that serum HBsAg levels are higher in
patients with active HBeAg-negative chronic hepatitis than
in inactive carriers, and that a single serum HBsAg level
may predict the clinical status of HBV infection [19,34e37].
These studies also revealed the association between HBsAg
levels and liver inflammation and fibrosis [19,37]. An Italian
study of HBeAg-negative carriers found that an HBsAg level
< 1000 IU/mL was strongly associated with the inactive
HBsAg carrier state [34]. Another Taiwanese study indicated that measuring HBsAg levels may improve the identification rate of patients who are at increased risk of
developing CHB-related complications [36]. The combined
use of HBV-DNA and serum HBsAg levels monitoring may
improve prediction of clinical stages and complications in
cross-sectional studies [35e37].
In our study, the serum HBsAg levels tested before the
patients received antiviral therapy were all <10,000 IU/mL
and lower levels were found with increasing age. The proportion of liver cirrhosis and HCC is lower in patients with
an HBsAg level < 100 IU/mL (p < 0.001 and p < 0.05,
respectively). The criterion that an HBsAg level < 100 IU/
mL, but not < 1000 IU/mL, had a high predictive value for
predicting freedom from cirrhosis and HCC at the time the
HBsAg level was examined. Using serum HBsAg levels to
predict CHB severity revealed a discrepancy between our
study results and those of European studies. This discrepancy may be due to differences in age or genotype. Most
longitudinal studies of inactive HBsAg carriers enrolled patients in their 30s or 40s and followed them for 3e20 years
[7]. These studies recruited few older patients in the late
stage of CHB infection. The serum HBsAg level can be
considered a surrogate marker for the number of infected
cells. As time progresses, a lower serum HBsAg level may
indicate less HBV replication or fewer infected hepatocytes
in patients with better prognosis. Lower serum HBsAg levels
in old age may occur in patients who were active carriers in
the early part of their life. However, the long-term effect
of HBV-DNA concentration fluctuation and the correlation
between HBV-DNA and serum HBsAg levels in older patients
require further study.
A genotype that might have an impact on HBsAg production is another factor that may affect the prediction of
clinical results using the serum HBsAg level. In fact, lower
HBsAg levels have been observed in East Asian patients
carrying HBV genotypes B and C [19]. In Taiwan, the major
genotypes of HBV are B and C, and the serum HBsAg levels
would be lower than those observed in European patients.
In a Taiwanese study, 23% of patients with HBeAgnegative and HBV-DNA-positive reactive hepatitis developed cirrhosis during the 9-year follow-up period [4]. In our
study, 30% of patients developed cirrhosis prior to enrollment. Fourteen percent (24/167) of patients with an HBsAg
< 100 IU/mL had cirrhosis; these patients may have severe
liver inflammation during the immune clearance stage.

P.-L. Lee et al.

Only 34.7% of patients had PNALT. However, the limitation
related to ALT in this study involves different frequencies of
ALT examination due to varying clinical severities. In daily
practice in Taiwan, the follow-up duration differs among
patients with and without cirrhosis. More than 60% of patients who underwent the HBV-DNA test had a serum level
> 2,000 IU/mL. Older patients in our study tended to
develop cirrhosis, and these results indicated that older
patients with active HBeAg-negative hepatitis would have a
lower chance of remission and need aggressive treatment.
The combined use of HBV-DNA and serum HBsAg levels
may improve the prediction in cross-sectional studies.
However, these results did not improve when we analyzed
the value of combined HBV-DNA and serum HBsAg levels in
the subgroup of patients who underwent HBV-DNA testing
(data not shown). Because HBsAg-positive patients in
Taiwan are not routinely screened for HBV-DNA levels, we
did not have these data available for all patients, which is a
study limitation. The other limitation of this study was that
data on other factors that may contribute to the development of cirrhosis (e.g., diabetes mellitus or autoimmune
hepatitis) were not available. Results from our study
showed that a single HBsAg serum level < 100 IU/mL may
predict favorable clinical results in older patients in the
late stage of CHB virus infection. Antiviral therapy may
affect the serum HBsAg level, and the effectiveness of
clinical outcome prediction using the serum HBsAg level
needs further study.

Conflicts of interest
All contributing authors declare no conflicts of interest.

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