CLB-08838; No. of pages: 7; 4C: Clinical Biochemistry xxx (2014) xxx–xxx
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Clinical Biochemistry journal homepage: www.elsevier.com/locate/clinbiochem
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Article history: Received 23 October 2012 Received in revised form 7 August 2014 Accepted 9 August 2014 Available online xxxx
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Keywords: Golgi membrane protein 73 Chronic hepatitis B Cirrhosis Hepatocellular carcinoma
Institute of Infectious Disease, Ditan Hospital, Capital Medical University, Beijing 100015, China Health Science Center, Peking University, Beijing 100083, China
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Objectives: To clarify the role of Golgi membrane glycoprotein 73 (gp73) in evaluating the progression of chronic hepatitis B virus (HBV) infection. Design and methods: Participants included 958 controls, 421 chronic hepatitis B, 944 hepatic cirrhosis, and 127 hepatocellular carcinoma (HCC) patients. All the patients, with the exception of the controls, were diagnosed HBsAg positive. Serum biomarkers, including gp73, alpha-fetoprotein (AFP), alpha-L-fucosidase, and Lens culinaris agglutinin-reactive fraction of AFP, were determined. Results: The patients with Hepatic cirrhosis gp73 levels over 150 ng/mL had an odds ratio of 3.21 (95% CI: 2.07–5.00). In hepatic cirrhosis patients, serum gp73 correlated with the Child–Pugh score. gp73 is a marker for diagnosing cirrhosis in the hepatitis populations. When the cut-off was set at 75.5 ng/mL, the sensitivity, specificity, and AUC were 75.6% (95% CI: 71.30%–79.62%), 60.3% (95% CI: 56.95%–63.63%) and 0.72 (95% CI: 0.69–0.75), respectively. Conclusion: The variation trend of gp73 in chronic liver disease may indicate that monitoring of serum gp73 is helpful to diagnose cirrhosis in population with chronic HBV infection. © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
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Introduction
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More than 90% of hepatocellular carcinoma (HCC) cases develop as a consequence of underlying liver diseases, and hepatic cirrhosis occurs in 80% of cases [1]. Globally, hepatitis B virus (HBV) infection is a most prevalent risk factor for the development of HCC [2]. Burden of HBVrelated HCC is still a major public health challenge, and liver cirrhosis is the seventh leading cause of death worldwide [3,4]. Although most HCC develops in the hepatic cirrhosis population, the correlation between HCC and cirrhosis is more likely to be multifactorial [5]. Generally, the diagnosis of HCC is greatly dependent on related imaging techniques. However, the major difficulty in imaging cirrhosis is the verification of hypervascular nodules (diameter b 2 cm), which often have nonspecific imaging characteristics [6]. Although ultrasound, computed tomography, and magnetic resonance imaging are effective methods for HCC diagnosis, the sensitivity for 1–2-cm HCC in combination with cirrhosis is very low [7]. In view of cost effectiveness, optimal screening approaches should be established to detect HCC in hepatic cirrhosis patients [8,9].
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Yong Qiao a,1, Jinglong Chen a,1, Xin Li a,1, Honglian Wei a, Fan Xiao a, Lusi Chang a, Renwen Zhang a,b, Xiaohua Hao a, Hongshan Wei a,⁎
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Serum gp73 is also a biomarker for diagnosing cirrhosis in population with chronic HBV infection
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⁎ Corresponding author at: Jingshun East Street 8, Chaoyang District, Beijing 100015, China. Fax: +86 10 84322620. E-mail address:
[email protected] (H. Wei). 1 They equally contributed to this work.
Many biological reactions happen during the development of HCC, including glycosylation [10,11], and although many studies focus on the diagnosis of HCC, definitive positive and negative markers are still absent. Alpha-fetoprotein (AFP) alone as a marker for diagnosis is strongly discouraged and its use in combination with ultrasound is controversial [12]. Recently, Golgi membrane glycoprotein 73 (gp73) has been proposed as a serum biomarker for HCC [13]. Its physiologic function, however, remains unknown. gp73, an integral membrane glycoprotein encoded by Golgi membrane protein 1 gene, localizes to the cis-Golgi and is not known to be secreted. However, proprotein convertase furin is capable of cleaving purified gp73 and resulting in gp73 secretion [14], although the clinical utility of this biomarker remains limited, largely because of the lack of quantitative information [15]. Serum gp73 is expressed at a higher level in HCC patients compared with healthy individuals [16,17]. Western blot assay suggested that gp73 had an equal to or greater predictive value compared with currently used markers, such as AFP [18,19]. Several studies also demonstrated that gp73 could also serve as a potential novel biomarker for prostate cancer [20,21], lung cancer [22], and seminomas [23]. In normal liver, gp73 is expressed in biliary epithelial cells but not in normal hepatocytes, while gp73 levels are dramatically upregulated in pathological livers. Increased gp73 expression in hepatocytes appears to be an important feature of advanced liver disease [24].
http://dx.doi.org/10.1016/j.clinbiochem.2014.08.010 0009-9120/© 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Please cite this article as: Qiao Y, et al, Serum gp73 is also a biomarker for diagnosing cirrhosis in population with chronic HBV infection, Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.08.010
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Statistical analysis
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Materials and methods
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Participants
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Results
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This study was approved by the Ethics Committee of Ditan Hospital (Beijing, China) and all the participants signed informed consent forms. All the patients were over 18 years (Table 1). Data were collected from all consecutive patients who fulfilled the clinical criteria for confirmed chronic hepatitis B, cirrhosis, and HCC, as established by the American Association for the Study of Liver Diseases (AASLD) [26], in Ditan Hospital (Beijing, China) from September 1st, 2009 to October 1st, 2010. For HCC, the enrollment criteria included that nodules larger than 2 cm which were hypervascular by any imaging method were regarded as HCC, and nodules 1–2 cm in size which were hypervascular by any two imaging techniques were also regarded as HCC. For cirrhotic patients, those admitted to our hospital at baseline (time 0) but without another follow-up were excluded. The length of follow-up was from admission to our hospital at baseline to the last medical examination in our hospital. Cirrhotic patients with a follow-up of less than one month were also excluded from our study. All individuals in the control group were healthy, and sera were free from HBsAg, anti-HCV, and antiHIV. All the serum samples from cirrhotic patients were obtained before drug therapy was implemented.
Pearson's chi-square test was applied to assess the correlation between serum gp73 and the predictive value of HCC in the cirrhotic patients. Unpaired independent Student's t test and one-way analysis of variance were performed to compare the difference(s) in serum gp73 level(s) between and among groups, respectively. To assess the role of gp73 as a diagnostic marker for cirrhosis or HCC, a receiver operating characteristic curve (ROC) was plotted and the area under the curve (AUC) was calculated to determine the effect of different gp73 serum level cut-off values for the different diagnoses. Linear correlation was used to determine the correlation between serum gp73 levels and albumin. P b 0.05 was considered statistically significant.
112
HBV DNA quantification
113 114 115 116
HBV DNA was determined with HBV real-time polymerase chain reaction reagents (Daan Co., China) according to the manufacturer's instructions, as previously described [27]. The linear dynamic range is approximately 5 × 102–5 × 109 copies/mL.
117 118
gp73, AFP, alpha-L-fucosidase (AFU), and Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) assays
119
122
Serum concentrations of AFP and gp73 were measured using chemiluminescent immunoassay kits (Hotgen Biotech Co., Beijing, China). Serum AFU activity was assayed using an AFU Assay kit (Mike Biotech Co., Sichuan, China). In brief, after being co-cultured with substrate
t1:1 t1:2
Table 1 The demographic data of the participants.
103 104 105 106 107 108 109 110
120 121
t1:3
Group
Sex
N
t1:4
Control
t1:5
Chronic hepatitis B
t1:6
Cirrhosis a
t1:7
HCC a
Male Female Male Female Male Female Male Female
539 419 252 169 708 236 105 22
t1:8
a
Numbers at baseline.
Age (Years)
P value
Mean ± SD
95% CI (%)
43.28 44.82 40.47 42.05 49.40 54.92 54.50 56.27
39.31–46.22 40.27–43.15 38.36–42.57 39.51–44.59 48.58–50.21 53.69–56.15 51.16–61.39 52.53–56.48
± ± ± ± ± ± ± ±
17.13 15.29 15.43 15.33 11.05 9.60 10.21 11.54
0.148 0.302 0.000 0.471
O
R O
P
125 126 127 128 129 130 131 132 133
136 137 138 139 140 141 142 143 144 145
D
102
More sensitivity but lower specificity of gp73 for diagnosis of HCC in the 147 cirrhotic population 148
E
100 101
To confirm the role of serum gp73 in diagnosing HCC in the cirrhotic population, we performed ROC analysis, in which a higher AUC reflects a higher ability to discriminate cirrhosis and HCC. Thus, we first compared the diagnostic differences of gp73, AFP, AFU, and AFP-L3 in the cirrhotic population at baseline. The results showed that, when compared with other markers, gp73 was the most sensitive to diagnose HCC in the cirrhotic population with a sensitivity of 45.25% (95% CI: 38.56%–52.06%) and a specificity of 66.94% (95% CI: 63.67%–70.10%) (Table 2). However, it had a limited discriminatory accuracy, with an AUC of only 0.59 (Fig. 1A). The AUC of gp73 was less than that of AFP (Fig. 1B) and AFP-L3 (Fig. 1C), similar to AFU (Fig. 1D).
149
Predictive value of gp73 for HCC diagnosis in cirrhotic patients
161
ROC analysis was used to determine whether serum gp73 and other markers are powerful to predict HCC in the cirrhotic population, as measured by the AUC. The primary values were the sensitivity, specificity, and positive and negative predictive values. During 1–11 months of follow-up, 94 out of 944 cirrhotic patients were confirmed to have HCC eventually. Actually, cirrhotic patients with gp73 levels above 150 ng/mL had a risk of developing HCC, with an odds ratio of 3.21 (95% CI: 2.07–5.00) (Table 3). In addition, AFP was also an efficient marker to distinguish HCC from cirrhosis when the serum concentration was set at 400 ng/mL (Table 3) [28]. Further, as shown in Table 2, gp73 was more sensitive than AFU for HCC diagnosis in the cirrhotic population. In contrast, AFP-L3 and AFU were inefficient to distinguish HCC from cirrhosis when the threshold was set at 10% and 40 U/L, respectively (Table 3). This contradicts recent reports that stated that AFP-L3 was a marker for HCC diagnosis with a higher specificity than AFP [29,30]. If AFP level was set at N 100 ng/mL, the relative level of AFP-L3 was measured as a control marker. Unexpectedly, the odds ratio was only 1.47 (95% CI: 0.67–3.21), significantly lower than that of AFP and gp73 (Table 3).
162
T
98 99
C
96 97
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94 95
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87 88
R
85 86
O
84
C
82 83
N
80 81
F
(α-L-fucopyranoside) in 0.1 mol/L NaH2PO4/Na2HPO4 buffer (pH7.0), fluorescence values of serum samples were read at 450 nm using a Hitachi 6000 Auto Biochemical Analysis Instrument (Hitachi Co., Tokyo, Japan). For AFP-L3, the serum was first isolated by lectin-affinity column, and Lens culinaris agglutinin selective elution was used to assay AFPL3 by chemiluminescent immunoassay. Samples with an AFP value exceeding 1000 ng/mL (upper limit of standard curve) were diluted by 10-, 100-, and 1000-fold and re-measured. Because AFP-L3 was not always reliable in the case of low serum AFP concentration, only samples with N100 ng/mL total AFP were analyzed for AFP-L3.
89 90
The main limitation of the present study is that the mean time of following-up was too short to elucidate the utility of gp73 for HCC screening in cirrhotic population. The other defect of the present study is that only a small part of cirrhotic patients received AFP-L3 and AFU analysis, consequently, difficulty to adequately show the validity differences among different serum markers. The sequential progression from regenerative nodules to well, moderately, and poorly differentiated HCC is now established; however, whether gp73 overexpression is an early warning sign for HCC in cirrhotic patients has not been determined [25]. The goal of this study is to illuminate the diagnostic and predictive role of serum gp73 for HCC in the cirrhotic population, and to evaluate the expression profile of gp73 after chronic HBV infection.
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Y. Qiao et al. / Clinical Biochemistry xxx (2014) xxx–xxx
Please cite this article as: Qiao Y, et al, Serum gp73 is also a biomarker for diagnosing cirrhosis in population with chronic HBV infection, Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.08.010
150 151 152 153 154 155 156 157 158 159 160
163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181
Y. Qiao et al. / Clinical Biochemistry xxx (2014) xxx–xxx t2:1 t2:2
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Table 2 Serum gp73 and other markers for HCC in the cirrhosis patients.
t2:3
Markers
N (Tested)
Cut-off
Sensitivity (%)
95% CI (%)
Specificity (%)
95% CI (%)
t2:4 t2:5 t2:6 t2:7
gp73 AFP AFP-L3 AFU
944 944 204 324
150 ng/mL 400 ng/mL 10% 40 U/L
45.25 22.17 42.42 36.21
38.56–52.06 16.88–28.23 32.55–52.77 27.49–45.65
66.94 97.53 83.81 72.60
63.67–70.10 96.25–98.46 75.35–90.28 66.00–78.54
F
C
201
E
199 200
gp73 is expressed in highly differentiated HepG2 hepatoma cells after adenovirus infection in vitro [34]. Increased gp73 is a common feature of hepatocytes and is triggered in response to inflammation, fibrosis, and dysplasia [35]. Because gp73 in HBV patients are upregulated, it seems reasonable to assume that either an inflammatory or a neoplastic process might be able to trigger gp73 expression in liver tissue [36,37].
R
197 198
R
195 196
204 205 206 207 208 209 210 211 212 213 214
Serum gp73 respectively correlates with HBV DNA, alanine aminotransferase 215 (ALT), and total bilirubin in the cirrhosis and HCC patients 216
N C O
193 194
U
191 192
O
To confirm the diagnostic role of serum gp73 in the progression of chronic hepatitis B, we assayed the serum gp73 levels in chronic hepatitis B, cirrhosis, and HCC patients, respectively. A total of 2460 serum samples were analyzed. The results revealed that serum gp73 level was varied in the progression of chronic HBV infection. The concentration interval of gp73 in each stage of liver disease including normal, CHB, cirrhosis, HCC was 48.46 ± 27.67 mg/mL (95% CI: 46.70– 50.21 mg/mL), 65.93 ± 55.71 mg/mL (95% CI: 60.67–71.21 mg/mL), 132.42 ± 103.33 mg/mL (95% CI: 125.48–139.37 mg/mL), and 161.22 ± 108.63 mg/mL (95% CI: 146.81–175.62 mg/mL) (Fig. 2A). It showed a gradually increasing tendency of serum gp73 accompanied by the development of liver disease after hepatitis B virus infection.
R O
190
202 203
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Serum gp73 is a marker to assess the progression of hepatitis B infection
186 187
D
189
184 185
Then, we investigated the correlation between Child–Pugh classification and serum gp73 level in the cirrhotic patients. As expected, the serum gp73 level in the patients with Child–Pugh B was significantly higher than those with Child–Pugh A, but lower than those with Child–Pugh C (Fig. 2B). Because the data support the hypothesis that the progression of HBV-related chronic liver disease is concomitant with increasing serum gp73 level, we speculate that serum gp73 may be a useful marker for diagnosing liver cirrhosis and therefore, ROC analysis was performed. We found that serum gp73 was a marker for diagnosing liver cirrhosis in the patients with HBV. The ROC analysis revealed that the ROC was 0.72 and the 95% CI is 0.71 to 0.79 in 431 patients with HBV and 852 patients with liver cirrhosis (Fig. 3).
T
188
As described by previous reports, AFU is also a useful marker for HCC diagnosis [31,32] when used in combination with AFP or ultrasonography [33]. To compare the diagnostic differences of AFU and gp73 in cirrhosis and HCC, 208 cirrhotic patients and 116 HCC patients also received an AFU test based on patient needs assessed by physicians at baseline. The results revealed that AFU had no predictive value for early diagnosis of HCC in the cirrhotic population (P = 0.87).
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Fig. 1. Specificities of various biomarkers for diagnosis of HCC in the cirrhotic participants. A. gp73; B. AFP; C. AFP-L3; D. AFU.
Please cite this article as: Qiao Y, et al, Serum gp73 is also a biomarker for diagnosing cirrhosis in population with chronic HBV infection, Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.08.010
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Table 3 The predictive value of gp73 and other markers for HCC diagnosis in cirrhotic patients at baseline.
gp73
t3:5
AFP
t3:6
AFP-L3
t3:7
AFU
Specificity (%) (95% CI)
66.98 (63.71–70.13)
61.29 (50.62–71.22)
3.78 (2.24–6.36)
5.23 (2.44–11.23)
11.70 (5.99–19.97)
97.53 (96.25–98.46)
1.33 (0.75–2.34)
1.47 (0.67–3.21)
33.33 (19.09–50.22)
74.58 (65.74–82.14)
1.07 (0.63–1.79)
1.09 (0.56–2.09)
29.63 (17.98–43.61)
72.04 (65.46–77.98)
correlated with HBV DNA copies (r = 0.25, P b 0.01) (Fig. 4A). Serum gp73 levels in the HBV DNA-positive patients were significantly higher than those in HBV DNA-negative patients (Fig. 4A). Furthermore, serum gp73 correlated with serum ALT in the cirrhosis and HCC populations (r = 0.21, P b 0.01) (Fig. 4B), and serum gp73 levels of patients with N18.8 μmol/L total bilirubin (Tbil) were significantly higher than those with b 18.8 μmol/L Tbil (Fig. 4C), displaying a correlation between gp73 and Tbil (r = 0.28, P b 0.01).
231
The multiple regression analysis of gp73, AFP, AFP-L3, and AFU for discriminating performance between HCC and cirrhosis
239 240
P
Because gp73 is expressed at a high level in hepatocytes of patients with viral hepatitis [38], we investigate whether factors, including HBV DNA, ALT, and total albumin (ALB), correlated with serum gp73 level in the cirrhosis and HCC patients. As expected, the results demonstrated that serum gp73 level was correlated with serum HBV DNA copies. In total, 37.25% (399/1071) of the cirrhosis and HCC patients were HBV DNA-positive at baseline. In the HBV DNA-positive group, the serum gp73 level was positively
E
D
The results suggested that the combination of gp73 and AFU or AFPL3 could not significantly improve the discriminating efficacy of AFP for diagnosing HCC in the cirrhotic population (Table 4), this may be at least partly due to only minority of cirrhotic patients received AFP-L3 or AFU test.
R
E
C
T
Discussion
R
230
Sensitivity (%) (95% CI)
3.21 (2.07–5.00)
O
228 229
Odds ratio (95% CI)
1.13 (1.07–1.19)
Although gp73 has been validated as a biomarker for diagnosing HCC in previous studies [37,38], it is still unclear whether this marker is better than other markers, such as AFP [25,39,40]. However, until now, few studies have been reported [25]. Another concern is that most HCCs occur on a basis of cirrhosis [5]. In view of this, it would be necessary to evaluate the potential value of gp73 in diagnosing and or predicting HCC in the cirrhotic population. Currently, AFP is the only available serological marker in clinic, but its diagnostic accuracy is unsatisfactory because of low sensitivity, despite a reliable specificity [41]. In a large-scale, retrospective study, we demonstrate that serum gp73 is a more sensitive marker than AFP for diagnosing HCC in cirrhotic patients, but the specificity was relatively lower. Based on this, in HBV-positive cirrhotic patients, serum gp73 in the course of HCC appears to be a promising complementary marker
C
226 227
Relative risk (95% CI)
338 (57) 606 (36) 32 (11) 912 (83) 43 (13) 114 (26) 75 (16) 190 (38)
N
224 225
N (Positive)
N150 ng/mL b150 ng/mL N400 ng/mL b400 ng/mL N10% b10% N40 U/L b40 U/L
U
223
Cut-off
F
t3:4
O
t3:3
R O
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Y. Qiao et al. / Clinical Biochemistry xxx (2014) xxx–xxx
Fig. 2. Serum gp73 levels for diagnosing cirrhosis. A. Serum gp73 levels in different stages of HBV infection; B. Serum concentration of gp73 in the cirrhotic patients with different Child–Pugh classification.
Fig. 3. The effects of serum gp73 in diagnosing liver cirrhosis in the 431 patients with HBV.
Please cite this article as: Qiao Y, et al, Serum gp73 is also a biomarker for diagnosing cirrhosis in population with chronic HBV infection, Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.08.010
232 233 234 235 236 237 238
241 242 243 244 245 246 247 248 249 250 251 Q6 252 253 254 255 256 257 258 259 260
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261
N C O
Fig. 4. HBV DNA, ALT, and Tbil respectively correlate with serum gp73 in the cirrhosis and HCC patients. A. Serum gp73 level correlates with HBV DNA copies; B. Serum gp73 level in patients with N40 U/L ALT is higher than those with b40 U/L ALT; C. Serum gp73 level in patients with N18.8 μmol/L Tbil is significantly higher than those with b18.8 μmol/L Tbil.
t4:1 t4:2
Table 4 The multiple regression analysis of gp73, AFP, AFP-L3, and AFU for discriminating performance between HCC and cirrhosis.
264 265 266 Q7 267 268 269
U
270
in the surveillance of HCC. Several reports confirmed the diagnostic role of gp73 in HCC [42,43] but not in the control population, including hepatitis patients and healthy subjects [19,44]. In the present study, we also observed that AFP played a better role in HCC diagnosis and prediction than AFP-L3, although supported by a recent study [13], is in contrast to previous reports [31,45,46]. We speculate that this is partly due to the choice of control populations and the varied follow-up period. Another difference could be attributed to a lower AUC for gp73 [16,25], which might be associated with different subject numbers in the groups [47].
262 263
Originally, we hypothesized that gp73 was better than or equivalent to AFP for prediction of HCC in a cirrhotic population. ROC analysis showed that gp73 displayed the highest sensitivity to predict HCC, followed by AFP, then AFP-L3 and AFU. Interestingly, we also found that the gp73 concentration was highest in the Child–Pugh class C group and lowest in the Child–Pugh class A group. Furthermore, serum gp73 was negatively correlated with serum album. However, an earlier study proposed by Mao et al. [36] reported that there was no correlation between the Child–Pugh score and gp73, which is somewhat different from our study. Based on our results, there are several
t4:3
Index
Model
AUC
Sensitivity
Specificity
t4:4 t4:5
gp73 + AFP gp73 + AFPa
x = −1.6994 + 0.00212(gp73) + 0.000022(AFP) x = −1.7188 + 0.3627(gp73) + 2.3605(AFP)
60.40% 64.30%
54.75% 56.56%
61.41% 66.12%
t4:6 Q1
a
gp73 ≥ 150 ng/mL vs. gp73 b 150 ng/mL, AFP ≥ 400 ng/mL vs. AFP b 400 ng/mL.
Please cite this article as: Qiao Y, et al, Serum gp73 is also a biomarker for diagnosing cirrhosis in population with chronic HBV infection, Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.08.010
271 272 273 274 275 276 277 278 279 280
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This study was supported by grants from the National Natural Science Foundation of China (Nos. 30671875 and 30872243). We also thank Dr. Qi Wang, Dr. Lianhe Lu and other colleagues for their technical assistance.
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factors that could cause such differences. Firstly, there were only 512 cases of liver cirrhosis patients in the study of Mao, but there were 944 cases in our study. Secondly, all the 944 liver cirrhosis patients in our study were HBV positive, whereas only 312 liver cirrhosis patients were HBV positive in the study of Mao. This could be another reason for the different results, since others not only have found a correlation between gp73 and liver disease progression, but also have confirmed that the upregulation of gp73 in hepatic cells is associated with hepatic cell viral replication [34]. Thirdly, 20% of the liver cirrhosis patients in the study of Mao [36] were non-virus infected (102/512), which might be responsible for the differences. To our knowledge, liver cirrhosis, a “final” common outcome of injury in the liver, is believed to be a critical factor leading to hepatic dysfunction. For years, hepatic histopathological examination has been considered to be the “gold standard” to assess fibrosis and cirrhosis. However, it is not favored for patients in many cases because of the invasive nature of the procedure. Consequently, serum markers for diagnosis of liver fibrosis and cirrhosis are becoming more and more attractive since they are less invasive. Recently, transient elastography has been performed with diagnostic accuracy for liver cirrhosis [48]. However, a high variation in the AUC was found in the diagnosis of significant fibrosis, most likely because it was dependent on the underlying liver disease [49]. Although our results highlight a key role of gp73 in diagnosing liver cirrhosis, whether gp73 is more accurate than currently used “direct markers” is still not clarified in the assessment of liver cirrhosis. The serum concentrations of “direct markers” reflect the progressive “speed” of fibrogenesis, rather than “grade” of liver fibrosis or cirrhosis [50,51]. Consequently, these markers may be useful to evaluate fibrosis progression rather than liver cirrhosis diagnosis. In the present study, we found that serum gp73 was negatively correlated with ALB, which suggests that serum gp73 might reflect the stage of cirrhosis, rather than the progressive “speed” of cirrhosis. Our results suggest that increased gp73 in chronic hepatitis B patients might be initiated by HBV infection and acceleration of chronic liver disease progression. Protein secretion from the Golgi complex is pH-dependent [52], suggesting that the increasing gp73 is a consequence of abnormal cytosolic pH. Homeostatic imbalance may result in the genesis of hepatitis, fibrosis, cirrhosis, and carcinoma, along with the progression of the liver disease. Actually, the variation of gp73 level in patients with chronic liver disease was positively correlated with the progression of the disease, reflecting progressive liver fibrosis and gradually aggravated liver function. Also, the variation trend of gp73 in chronic liver disease may suggest a disorder of Golgi homeostasis or secretion pathway in hepatocytes.
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Please cite this article as: Qiao Y, et al, Serum gp73 is also a biomarker for diagnosing cirrhosis in population with chronic HBV infection, Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.08.010
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[38] Fimmel CJ, Wright L. Golgi protein 73 as a biomarker of hepatocellular cancer: development of a quantitative serum assay and expression studies in hepatic and extrahepatic malignancies. Hepatology 2009;49:1421–3. [39] Iftikhar R, Kladney RD, Havlioglu N, Schmitt-Gräff A, Gusmirovic I, Solomon H, et al. Disease- and cell-specific expression of GP73 in human liver disease. Am J Gastroenterol 2004;99:1087–95. [40] Maitra A, Thuluvath PJ. GP73 and liver disease: a (Golgi) complex enigma. Am J Gastroenterol 2004;99:1096–8. [41] Giannelli G, Antonaci S. New frontiers in biomarkers for hepatocellular carcinoma. Dig Liver Dis 2006;38:854–9. [42] Norton PA, Comunale MA, Krakover J, Rodemich L, Pirog N, D'Amelio A, et al. Nlinked glycosylation of the liver cancer biomarker GP73. J Cell Biochem 2008;104: 136–49. [43] Wright LM, Yong S, Picken MM, Rockey D, Fimmel CJ. Decreased survival and hepato-renal pathology in mice with C-terminally truncated GP73 (GOLPH2). Int J Clin Exp Pathol 2009;2:34–47. [44] Riener MO, Stenner F, Liewen H, Hellerbrand C, Bahra M, Kristiansen G. Alphafetoprotein and serum golgi phosphoprotein 2 are equally discriminative in detecting early hepatocellular carcinomas. Hepatology 2009;50:326. [45] Tamura Y, Igarashi M, Kawai H, Suda T, Satomura S, Aoyagi Y. Clinical advantage of highly sensitive on-chip immunoassay for fucosylated fraction of alpha-fetoprotein in patients with hepatocellular carcinoma. Dig Dis Sci 2010;55:3576–83.
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Please cite this article as: Qiao Y, et al, Serum gp73 is also a biomarker for diagnosing cirrhosis in population with chronic HBV infection, Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.08.010
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