|Year : 2016 | Volume
| Issue : 1 | Page : 152-159
Golgi protein 73 versus alpha fetoprotein as a marker for hepatocellular carcinoma
Mariam A Fouad1, Emad F Haleim1, Waleed F Azeim1, Dalia HA Elela1, Osama H Abdelsalam2
1 Clinical Pathology Department, Faculty of Medicine, El Menoufia University, Egypt
2 Liver Surgery Department, National Liver Institute, Faculty of Medicine, Menoufia University, Egypt
|Date of Submission||19-Mar-2014|
|Date of Acceptance||09-May-2014|
|Date of Web Publication||18-Mar-2016|
Mariam A Fouad
MBBCh, Faculty of Medicine, El Menoufia University, Yassin AbdEl Ghaffar Street, Shebin El Kom, 32521 El Menofia
Source of Support: None, Conflict of Interest: None
The aim of this work was to assess the clinical utility of Golgi protein 73 (GP73) among Egyptian hepatocellular carcinoma (HCC) patients in comparison with α-fetoprotein (AFP). In addition, the level of GP73 was evaluated after surgical resection of HCC.
Serum Golgi protein 73 (sGP73) is a promising biomarker for detection of HCC.
Patients and methods
This study included 76 patients; 38 of them had proved HCC (10 of them were followed up after hepatectomy to detect the level of GP73 after treatment), 25 patients had chronic liver diseases (CLDs) and 13 apparently healthy individuals were considered as controls. Clinical examination, abdominal ultrasonography and triphasic computed tomography for focal lesion were performed. Liver function tests were performed using Synchron Cx9 ALX Clinical Autoanalyzer, serum AFP was measured using ELISA method and hepatitis markers and GP73 were determined by ELISA kit for GP73.
There was highly statistically significant difference in GP73 between HCC and the control group and also between HCC and the CLD group. Moreover, GP73 is significantly lower after hepatectomy. For discrimination of HCC from healthy control, receiver operating characteristic curve showed that sGP73 levels had area under the receiver operating characteristic (AUROC) curve of 0.89 [95% confidence interval (CI) 0.81-0.98)] and sensitivity of 76.3% and specificity of 92.3% at a cutoff point 192 ng/l, whereas AFP had AUROC curve of 0.83 (95% CI 0.71-0.95) and sensitivity of 73.7% and specificity of 61.5% at a cutoff point 10.5 ng/ml. For discrimination of HCC from CLD, receiver operating characteristic curve showed that the sGP73 levels had the AUROC curve of 0.88 (95% CI 0.79-0.96) and sensitivity of 76.3% and specificity of 84% at a cutoff point 195 ng/l, whereas AFP had AUROC curve of 0.83 (95% CI 0.72-0.93) and sensitivity of 73.7% and specificity of 68% at a cutoff point 10.5 ng/ml.
GP73 expression is highly increased in HCC patients. Its diagnostic performance is superior to that of AFP and is a useful marker for follow-up of HCC patients after surgical hepatectomy.
Keywords: Enzyme-linked immunosorbent assay, Golgi protein 73, α-fetoprotein, hepatocellular carcinoma
|How to cite this article:|
Fouad MA, Haleim EF, Azeim WF, Elela DH, Abdelsalam OH. Golgi protein 73 versus alpha fetoprotein as a marker for hepatocellular carcinoma. Menoufia Med J 2016;29:152-9
|How to cite this URL:|
Fouad MA, Haleim EF, Azeim WF, Elela DH, Abdelsalam OH. Golgi protein 73 versus alpha fetoprotein as a marker for hepatocellular carcinoma. Menoufia Med J [serial online] 2016 [cited 2019 Dec 7];29:152-9. Available from: http://www.mmj.eg.net/text.asp?2016/29/1/152/179007
| Introduction|| |
Hepatocellular carcinoma (HCC) is the most common form of liver cancer and is the third leading cause of cancer-related deaths worldwide . The global distribution varies by region because of factors at the origin of the disease. HCC is an end result of some chronic infections with hepatitis B virus (HBV) or hepatitis C virus (HCV) [2,3]. Treatment options for HCC are very limited, as it is often being diagnosed at a late stage . The increasing incidence of HCC worldwide has sparked a new interest in HCC serum markers. α-Fetoprotein (AFP), together with hepatic ultrasonography, is the most common marker used in clinical practice to detect HCC, but the clinical value of AFP is challenged in recent years due to its low sensitivity and specificity ,. Golgi protein 73 (GP73) is a resident Golgi-specific membrane protein expressed by biliary epithelial cells in normal liver, and its expression is increased markedly in chronic liver diseases (CLDs), especially in HCC cells . There have been studies reporting the use of serum Golgi protein 73 (sGP73) as a serum marker for HCC, but the results are heterogeneous and even conflicting. Studying this marker for its clinical utility among the Egyptian HCC patients may help to find a novel serologic marker with better sensitivity and specificity compared with AFP. In this study, both GP73 and AFP showed comparable sensitivities to differentiate HCC from both CLD and normal controls groups, but GP73 showed higher specificity. Combining both markers may improve the overall diagnostic performance to diagnose HCC and to differentiate it from CLDs; hence, testing the clinical utility of both markers in double combination is recommended. In addition, comparing the GP73 serum level with some of the prognostic factors of HCC can help to determine its role as a prognostic parameter for HCC.
| Aim|| |
The aim of this study was to assess the clinical utility of GP73 among Egyptian patients in comparison with AFP. In addition, the level of GP73 was evaluated after surgical resection of HCC.
| Patients and methods|| |
The study was conducted on 76 patients selected from the Hepatology Department of National Liver Institute, Menoufyia University who were divided into three groups:
(1) Group I: this group included 38 patients with HCC. There were 35 men and three women with a mean age ± SD of 52.68 ± 8.80 years. Ten of them were followed after hepatectomy to detect the level of GP73 after treatment.
(2) Group II: this group included patients with CLDs. They were classified into two subgroups:
(a) Liver cirrhosis (n = 15): this subgroup included 15 patients with liver cirrhosis, 10 men and five women with a mean age ± SD of 51.68 ± 6.85 years.
(b) Chronic hepatitis (n = 10): this subgroup included 10 patients with chronic hepatitis, eight men and two women with a mean age ± SD of 51.68 ± 6.85 years.
(3) Group III (the control group): this group included 13 apparently healthy individuals who served as a control group; there were 10 men and three women with a mean age ± SD of 51.38 ± 9.91 years.
Patients were selected with respect to the following exclusion criteria: none of the patients had bacterial or other viral infection, chronic renal damage, insulin-dependent diabetes mellitus and other malignant diseases. The patients undergoing interferon administration or immunosuppressive therapy were also excluded from this study.
Both patients and control groups were subjected to the following:
- Full history taking and thorough clinical examination.
- Abdominal ultrasonography and ultrasound-guided liver biopsy were performed by true-cut needle or liver biopsy gun for the cirrhotic patients when possible.
- Triphasic computed tomography for patients with focal lesion.
- The following laboratory investigations were performed. Liver function tests including alanine transaminase (ALT), aspartate aminotransferase (AST), serum albumin and total and direct bilirubin were performed using Synchron Cx9 ALX Clinical Autoanalyzer (Beckman Coulter, Instruments, Fullerton, California, USA). Prothrombin concentration was measured on the Behring Fibrintimer II (Dade Behring Marburg GmbH, Marburg, Germany) in addition to international normalized ratio (INR).
- Serum AFP was measured using the commercially available enzyme-linked immunosorbent assay (ELISA) kit. ELISA method kit was supplied by Glory Science Co. (Immunospec Corporation, Canoga Park, California, USA).
- Hepatitis markers (HBsAg, anti-HBc and HCV antibody) determination by direct sandwich assay, using the ELISA kit supplied by Adltis (Germany).
- GP73 was determined using the commercially available ELISA kit supplied by Glory Science Co. (Del Rio, Texas, USA). The kit uses a double-antibody sandwich ELISA to assay the level of humanGP73 in samples. GP73 is added to monoclonal antibody enzyme well, which is precoated with humanGP73 monoclonal antibody and incubated; thereafter, GP73-labelled antibodies and enzyme are added to form immune complex followed by incubation and washing again to remove the uncombined enzyme. Thereafter, chromogenic solution is added so that the colour of the liquid changes into blue, and by the effect of acid the colour finally becomes yellow. The chroma of colour and the concentration of the human substance GP73 of sample were positively correlated. The concentration of GP73 in the samples was then determined by comparing the optical density of the samples with the standard curve.
Data are expressed as mean ± SD. The SPSS (version 12.0; SPSS Inc., Chicago, Illinois, USA) computer program was used for statistical analysis. The ν2 -test was used to study the association between two qualitative variables. The Mann-Whitney U-test (nonparametric test) is a test of significance used for comparison between two groups not normally distributed having quantitative variables. The Kruskal-Wallis test (nonparametric test) is a test of significance used for comparison between three or more groups not normally distributed (if one or both variables are skewed) having quantitative variables. The Wilcoxon signed-rank test is a nonparametric statistical hypothesis test used when comparing two related samples, matched samples, or repeated measurements on a single sample to assess whether their population mean ranks differ. Correlation coefficients (r) were calculated using Pearson's correlation analysis. P value was significant at less than 0.05. Sensitivity, specificity and the area under the receiver operating characteristic (AUROC) curve were determined.
| Results|| |
Comparison was made between the three studied groups with respect to AFPs and GP73. [Table 1] shows that there was highly statistically significant difference in AFP and GP73 between the HCC group and the CLD group (P < 0.001). There was highly statistically significant difference in AFP and GP73 between the HCC group and the control group (P < 0.001). There was no statistically significant difference in AFP and GP73 between the CLD group and the control group (P > 0.05).
|Table 1: Comparison between the three studied groups with respect to á-fetoproteins and Golgi protein 73|
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Correlations study between GP73 and the other studied parameters in [Table 2] showed highly significant positive correlations between GP73 and both AST and AFP (P < 0.001) and significant positive correlations between GP73 and ALT, alkaline phosphatase (ALP) and total and direct bilirubin. There was no significant correlation between GP73 and age, albumin and INR.
|Table 2: Spearman's correlation between Golgi protein 73 and other parameters|
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In [Table 3], the mean ± SD of AFP in the HCC patients before treatment was 44.76 ± 90.08 and the mean ± SD of GP73 in the HCC patients before treatment was 270.0 ± 134.68.
|Table 3: Comparison of á-fetoprotein and Golgi protein 73 in a group of hepatocellular carcinoma patients before|
and after treatment
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The mean ± SD of AFP in HCC patients after treatment was 12.80 ± 8.34 and the mean ± SD of GP73 in HCC patients after treatment was 143.0 ± 63.43.
There was a statistically significant difference in the level of AFP before and after treatment (P < 0.001).
There was a statistically significant difference in the level of GP73 before and after treatment (P < 0.001). For discrimination of the HCC group from healthy controls, receiver operating characteristic (ROC) curve showed that the sGP73 levels had the AUROC curve of 0.89 [95% confidence interval (CI) 0.81-0.98], a sensitivity of 76.3% and a specificity of 92.3%; the diagnostic accuracy was 80.4%; positive predictive value was 96.7%; and negative predictive value was 57.1% at cutoff point 192 ng/l. However, AFP had an AUROC curve 0.83 (95% CI 0.71-0.95), a sensitivity of 73.7% and a specificity of 61.5%; the diagnostic accuracy was 70.6%; positive predictive value was 84.8%; and negative predictive value was 44.4% at cutoff point 10.5 ng/ml.
For discrimination of the HCC group from the CLD patients, ROC curve showed that the sGP73 levels had the AUROC curve of 0.88 (95% CI 0.79-0.96), a sensitivity of 76.3% and a specificity of 84%; the diagnostic accuracy was 83.3%; positive predictive value was 87.8%; and negative predictive value was 70% at cutoff point 195 ng/l. However, AFP had an AUROC curve of 0.83 (95% CI 0.72-0.93), a sensitivity of 73.7% and a specificity of 68%; the diagnostic accuracy was 71.4%; positive predictive value was 77.8%; and negative predictive value was 63% at cutoff point 10.5 ng/ml [Figure 1],[Figure 2] and [Figure 3] and [Table 4] and [Table 5],[Figure 4] and [Figure 5].
|Figure 1: Receiver operating characteristic curve of α-fetoprotein (ng/ml) and Golgi protein 73 (GP73) (ng/l) for discrimination of hepatocellular carcinoma from chronic liver disease patients.|
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|Figure 2: Receiver operating characteristic curve of α-fetoprotein (ng/ml) and Golgi protein 73 (GP73) (ng/l) for discrimination of hepatocellular carcinoma from healthy c ontrols.|
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|Figure 3: Comparison of α-fetoprotein and Golgi protein 73 (GP73) in a group of hepatocellular carcinoma patients before and after treatment.|
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|Table 4: Diagnostic performance of á-fetoprotein and Golgi protein 73 for discrimination of hepatocellular carcinoma|
from healthy controls
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|Table 5: Diagnostic performance of á-fetoprotein and Golgi protein 73 for discrimination of hepatocellular carcinoma|
from chronic liver disease patients
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| Discussion|| |
HCC is the most common form of liver cancer and is the third leading cause of cancer-related deaths worldwide. Treatment options for HCC are very limited, as it is often diagnosed at a late stage .
Therefore, the use of AFP as a primary screening test for HCC has been questioned; hence, more sensitive and specific serum biomarkers for HCC are desired .
However, Li et al.  tried to improve the detection rate of HCC using the ultrasonography and several biomarkers such as DCP, AFP-L3, human hepatocyte growth factor, and insulin-like growth factor-1, which were promising, but none of these markers have been validated enough for clinical use. Thus, there is an urgent need for new biomarker for early detection of HCC.
The need for closer monitoring of patients with chronic hepatitis who have a high risk of developing HCC during the course of the disease has long been stated. In these patients, AFP has been a particularly unsatisfactory screening tool for early detection of HCC .
Studies have identified GP73 [also named Golgi phosphoprotein 2 (GOLPH2)] as a HCC serum marker. GP73 is a 400-amino acid 73 kDa transmembrane glycoprotein that normally resides within the cis-Golgi complex. Its mRNA was first identified in a search for upregulated hepatic genes in a patient with syncytial giant cell hepatitis .
Although upregulated, GP73 was initially identified in hepatic viral infections with unknown function . Subsequent studies showed that GP73 serum level is elevated in viral and nonviral liver diseases, including hepatitis, cirrhosis and HCC, and also in nonliver malignancies .
In the present study, we compared the level of GP73 and AFP in 76 serum samples from patients with various benign and malignant liver diseases and healthy people as controls to find its sensitivity and specificity in early detection of HCC compared with conventional markers such as AFP serum levels; in addition, samples from patients with HCC were collected before and after hepatectomy.
In the current study, the serum levels of AFP are significantly elevated in CLDs and more elevated in HCC patients (P < 0.001).
Our results agreed with those of El Shafie et al.  who reported that the serum levels of AFP are significantly elevated in CLDs and more elevated in HCC patients (P < 0.001).
In addition, we found that there was no statistically significant difference in GP73 between the CLD group and the control group (P > 0.05).
This is in agreement with the study by Mao et al.  who found that the elevation of sGP73 is mildest in HBV carriers, moderate in patients with cirrhosis and marked in patients with HCC. Therefore, sGP73 can be used to monitor disease progression from HBV infection to cirrhosis to HCC. Moreover, they found that both liver benign tumours and non-HCC liver malignant lesions had elevated sGP73, although the magnitude is much smaller than that in HCC. sGP73 can therefore be a useful tool in determining the nature (benign vs. HCC) of hepatic tumours. Furthermore, patients with nonliver cancers also had moderate elevation of sGP73, none of which, however, reached the level identified for HCC patients.
In contrast to the current study, El Shafie et al.  reported that the serum levels of GP73 were significantly elevated in the CLD group compared with the healthy control group. This difference may be due to our CLD group that included cirrhotic and chronic hepatitis patients, but their CLD group included cirrhotic patients only.
The present study also revealed that there was high statistically significant difference in GP73 between the HCC group and the control group (P < 0.001), and also there was high statistically significant difference in GP73 between the HCC group and the CLD group (P < 0.001).
This was supported by the study by Marrero et al.  who reported that sGP73 levels were significantly increased in patients with HCV-related HCC in comparison with cirrhotic controls. Similar results were reported in a Chinese study on patients with predominantly HBV-related liver cancer.
Mao et al.  showed that the sGP73 levels in HCC patients who were HBV positive were significantly higher than those of HBV carriers, patients with nonliver diseases, and healthy controls.
Tian et al.  reported that sGP73 in HCC was higher than in CLDs, and in both groups it was higher than those in healthy individuals.
These results were disappointing with two previous studies; in the first study, sGP73 was found to be elevated in patients with liver disease but did not distinguish between HCC, cirrhosis and chronic hepatitis . In the second study, which was reported in an abstract form, sGP73 was surprisingly found to be decreased in HCC patients .
Other interesting findings in our study are that there is a significant decrease in the level of GP73 in group HCC patients before and 5 days posthepatectomy (P < 0.05).
Mao et al.  showed that, in a few HCC patients, the GP73 levels were not markedly lower a week after surgical resection but became lower 1.5-2 years after surgery. However, AFP levels usually decrease substantially within a week postresection. This result demonstrates that sGP73 levels change slower than serum AFP levels.
Our results are in agreement with those of Mao et al.  who demonstratedsGP73 values after surgical resection of tumours in patients with HCC. GP73 in patients with HCC decreased markedly following hepatectomy. sGP73 decreased after hepatectomy and returned to high levels after HCC relapse between 3 and 18 months. Hence, surgical resection of the tumour results in diminished sGP73 levels, and tumour recurrence correlates with the recurrence of elevated GP73 in the blood. Reappearance of sGP73 indicates the existence of tumour lesions, and thus may serve as an indicator for the recurrence of HCC.
The correlation study between GP73 and the other studied parameters revealed highly significant positive correlations between GP73 and both AST and AFP (P < 0.001) and significant positive correlations between GP73 and ALT, ALP and total and direct bilirubin. There were no significant correlations between GP73 and age and INR.
This in agreement with the finding of Tian et al.  who reported that sGP73 in liver cirrhosis (LC) patients with Child-Pugh class A was lower than those in class B and C, and GP73 correlated with AST, AST/ALT, albumin, albumin/globulin ratio (A/G) and ALP in liver cirrhosis.
Furthermore, El Shafie et al.  revealed that a significant correlation was found between sGP73 level and prognostic markers of LC (AST, ALT, serum albumin and Child score).
This study showed that sGP73 levels were significantly higher in patients with HCC compared with those with CLD. sGP73 levels had an AUROC curve of 0.88 (95% CI 0.79-0.96), a sensitivity of 76.3% and a specificity of 84%, whereas AFP had an AUROC curve 0.83 (95% CI 0.72-0.93) and a sensitivity of 73.7% and a specificity of 68% at cutoff point 195 ng/l and 10.5 ng/ml for GP73 and AFP, respectively. This demonstrated the utility of GP73 in the diagnosis of HCC in patients with normal or mildly elevated AFP, and the performance of GP73 as determined by the AUROC curve was found to be better than AFP.
These findings are in agreement with those of Marrero et al.  who showed that sGP73 levels were significantly higher in patients with HCC compared with those with cirrhosis. sGP73 levels had an AUROC curve of 0.79 (95% CI 0.72-0.82) and a sensitivity of 69% and a specificity of 75%, whereas AFP had an AUROC curve of 0.61 (95% CI 0.59-0.71) and a sensitivity of 30% and a specificity of 96%. sGP73 levels above the optimal cutoff were found in 62 and 71% of HCC patients who had AFP levels below 20 and 100 ng/ml, respectively, demonstrating the utility of GP73 in the diagnosis of HCC in patients with normal or mildly elevated AFP, and the performance of GP73 as determined by the AUROC curve was found to be better than AFP. The findings suggest an advantage of GP73 over AFP as a serum marker for early detection of HCC.
Mao et al.  showed that the sGP73 levels in HCC patients who were HBV positive were significantly higher than those of HBV carriers, patients with nonliver diseases and healthy controls. There was no difference in GP73 levels between healthy controls and patients with nonliver diseases (P = 0.2925). The sensitivity of GP73 for the diagnosis of HCC was 76.9%, which was significantly higher than that of AFP 48.6%. The specificity of GP73 for the diagnosis of HCC was 92.9%, which was significantly higher than that of AFP 75%. In the Mao and colleagues' study, nearly 35.1% of the patients with HCC were AFP-negative (<25 ng/l).
Mao et al.  reported that sGP73 had a higher sensitivity and specificity in the diagnosis of HBV-related HCC than AFP, and that it could be a new effective HCC tumour marker in Chinese patients.
Hu et al.  studied ROC curves comparing all HCC patients in Chinese patients and showed that the HBV-related HCC AUROC curve for GP73 was 0.89 (95% CI 0.82-0.97), with a sensitivity of 77.4% and a specificity of 83.9%, whereas the AUROC curve for AFP was 0.77 (95% CI 0.65-0.89), with a sensitivity of 48.4% and a specificity of 96.8%. The findings suggested that GP73 may be more useful as a serum marker for the detection of HCC compared with AFP.
Tian et al.  reported that GP73 had a sensitivity of 75.8% and specificity of 79.7%, with the AUROC curve of 0.844 as against 0.812 for AFP with a sensitivity of 95.2% and specificity of 47.1%; in detecting early HCC, the AUROC curve of AFP/GP73 was 0.804 versus 0.766 for AFP alone.
Riener et al.  concluded that GP73 is not a general HCC serum tumour marker but could rather be a valuable complementary tool in the surveillance of patients at risk. The data presented in Riener et al.'s  study provide further evidence that GP73 protein is strongly expressed in HCC and bile duct carcinoma tissues and is secreted into the blood. Possibly, it is either involved in post-translational protein modification, transport of secretory proteins, cell signalling regulation, or simply maintenance of Golgi apparatus function. GP73 has several potential glycosylation sites and up to 75% of GP73 secreted from hepatocytes is fucosylated . Endosomal trafficking of the normally membrane-bound GP73 leads to secretion into the blood, making it a potential serum biomarker for HCC .
Furthermore, El Shafie et al.  demonstrated that the sensitivity and specificity of GP73 for HCC were superior to those of AFP, especially in early HCC, in our study; GP73 had a sensitivity of 87% and a specificity of 95% at the optimal cutoff value of 7.62 ng/ml. The AUROC curve was 0.87.
| Conclusion|| |
Serum level of GP73 is highly increased in HCC patients in comparison with either the benign liver diseases or the healthy controls. Gp73 has a better diagnostic performance than AFP for detection of HCC. Gp73 is also a valuable serum marker for follow-up of HCC patients after surgical treatment.
Finally, in addition to AFP, measurement of sGP73 can further improve the diagnosis and follow-up of HCC, which is one of the most serious malignancies all over the world.
| Acknowledgements|| |
Conflicts of interest
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]