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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 30  |  Issue : 4  |  Page : 1037-1043

Evaluation of Midkine and Golgi protein 73 as diagnostic biomarkers in hepatocellular carcinoma patients


1 Department of Medical Microbiology and Immunology, Faculty of Medicine, Menoufia University, Shebin Elkom, Menoufia, Egypt
2 Department of Hepatic Medicine, Liver Institute, Menofia University, Shebin Elkom, Menoufia, Egypt
3 Department of Microbiology, Shibin El Koom Teaching Hospital, Shebin Elkom, Menoufia, Egypt

Date of Submission14-Jun-2017
Date of Acceptance13-Jul-2017
Date of Web Publication04-Apr-2018

Correspondence Address:
Ebtehal M Galbat
Department of Microbiology, Shibin El Koom Teaching Hospital, Shebin Elkom, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_427_17

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  Abstract 


Objective
The aim of this work was to assess the clinical utility of Midkine (MDK) and Golgi protein 73 (GP73) among Egyptian hepatocellular carcinoma (HCC) patients in comparison with α-fetoprotein (AFP).
Background
Serum MDK and serum Golgi protein 73 (sGP73) are promising biomarkers for the detection of HCC.
Patients and methods
This study included 96 patients; 40 of them had proved HCC, 36 patients had chronic liver diseases and 20 apparently healthy individuals were considered as controls. Clinical examination, abdominal ultrasonography, and triphasic computerized tomography for focal lesion were performed. Liver function tests, hepatitis markers and serum AFP were measured. Serum MDK and GP73 levels were determined by enzyme-linked immunosorbent assay.
Results
There was a high statistically significant difference in MDK and GP73 between HCC and the control group. For the diagnosis of HCC, the receiver operating characteristic (ROC) curve showed that serum MDK and GP73 levels had an area under the receiver operating characteristic (AUROC) curve of (1.00, 0.952), sensitivity of (100%, 90%) and specificity of 88.9% and 83.3% at a cutoff point of 1585.0 pg/l, 42.5 ng/l, respectively. For early diagnosis of HCC, the ROC curve showed that the serum MDK and GP73 levels had the AUROC curve of 0.869 and 0.941, sensitivity of 88.9 and 94.4% and specificity of 79.5 and 83.3% at a cutoff point of 3825 pg/l and 84.5 ng/l, respectively.
Conclusion
MDK and GP73 serum levels are highly increased in HCC patients. Their diagnostic performance is superior to that of AFP.

Keywords: enzyme-linked immunosorbent assay, Golgi protein 73, hepatocellular carcinoma, Midkine


How to cite this article:
Makled AF, ElAskary SA, ElKhyat AH, Gomaa AI, Galbat EM. Evaluation of Midkine and Golgi protein 73 as diagnostic biomarkers in hepatocellular carcinoma patients. Menoufia Med J 2017;30:1037-43

How to cite this URL:
Makled AF, ElAskary SA, ElKhyat AH, Gomaa AI, Galbat EM. Evaluation of Midkine and Golgi protein 73 as diagnostic biomarkers in hepatocellular carcinoma patients. Menoufia Med J [serial online] 2017 [cited 2018 Jul 21];30:1037-43. Available from: http://www.mmj.eg.net/text.asp?2017/30/4/1037/229222




  Introduction Top


Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third most frequent cause of cancer-related death. In Egypt, HCC represents 75% of malignant liver tumors[1].

HCC commonly arises against a background of chronic liver disease (CLD). In Egypt, HCC is associated with hepatitis C viral (HCV) infections, as it has the highest prevalence of HCV in the world with ∼13.8% of the population infected and seven million persons with chronic HCV liver disease[2].

Surveillance strategies for the detection of early HCC are necessary. For more than 40 years, the most common marker used in clinical practice has been α-fetoprotein (AFP), which is combined with hepatic ultrasonography. AFP is considered to be the gold standard serum marker for screening of patients who are at high risk of HCC, as well as for monitoring of treatment response; however, the clinical value of AFP has been questioned due to its low sensitivity and specificity[3]. As the overall survival of patients with cirrhosis has improved and the global incidence of HCC has continued to increase, strategies for early detection of HCC are urgently required[4].

Midkine (MDK) is a heparin-binding growth factor, strongly expressed during embryogenesis the expression of which is weak or undetectable in normal adult tissues[5]. However, MDK is involved in inflammatory response, in wound repair, and also in carcinogenesis. MDK is overexpressed in several types of cancer, including gastric, pancreatic, and colorectal cancer[6].

MDK is overexpressed in HCC and can promote HCC cell proliferation and invasion. It is also involved in the angiogenesis and tumorigenesis of HCC[7].

Golgi protein 73 (GP73) is a type II Golgi transmembrane protein with an estimated molecular weight of 73 kDa. GP73 is expressed primarily by the bile duct epithelial cells, and rarely by the hepatocytes of the normal human liver. Upregulated GP73 expression was reported in HCC patients, and its expression was suggested as a potential HCC serum marker[8]. Many studies have reported that the sensitivity and specificity of GP73 were higher than AFP. Thus, GP73 has been hypothesized to represent a novel serum marker for early HCC[9].

Studying MDK and GP73 for their clinical utility among the Egyptian HCC patients may help to find a novel serologic marker with better sensitivity and specificity compared with AFP.

This study aimed to assess the clinical utility of serum MDK and GP73 levels in HCC diagnosis, and to correlate and compare their levels with the laboratory tests, radiological and pathological parameters in the diagnosis of HCC.


  Patients and Methods Top


The study was conducted from September 2015 to July 2016 at Menoufia University Hospitals (Egypt). After approval of the Research and Ethics Committee of Menoufia University, all participants gave written informed consent before inclusion into the study who were divided into three groups: group I that included 40 patients were diagnosed as HCC (34 men and six women) selected from the Oncology Clinic, Liver Institute at Menoufia University Hospitals; group II included 36 patients with CLD (31 men and five women) admitted to the Tropical Medicine Department at Menoufia University Hospitals and Shebin El-Koom Teaching Hospital and group III included 20 age-matched and sex-matched apparently healthy individuals.

Patients were selected with respect to the following exclusion criteria: none of the patients had focal hepatic lesions other than HCC (cholangiocarcinoma, hemangioma, hepatoblastoma, metastatic focal lesions, etc.), malignancy elsewhere, chronic renal damage, and patients with administration of immune suppressive therapy.

All patients were subjected to full medical history taking, thorough clinical examination, and laboratory investigations including complete blood picture, complete liver and kidney profile, viral liver markers, serum AFP and serum MDK, and GP73 by enzyme-linked immunosorbent assay (ELISA).

MDK serum levels were measured by ELISA according to the manufacturer's instructions using Boster's Human MDK PicoKine ELISA Kit (Boster Biological Technology, 3942 B Valley Ave, Pleasanton, California, USA). Boster's Human MDK ELISA Kit is based on standard sandwich ELISA technology[10]. A monoclonal antibody specific for MDK has been precoated on to 96-well plates. Standards and test samples were added to the wells. A biotinylated detection polyclonal antibody specific for MDK will be added subsequently and then followed by washing with PBS buffer. Avidin–biotin–peroxidase complex was added and unbound conjugates will be washed away with PBS or TBS buffer. Horseradish peroxidase substrate Tri-Methyl Phosphate (TMB) was used to visualize horseradish peroxidase enzymatic reaction. The density of yellow is proportional to the human MDK amount of sample captured in plate.

GP73 serum levels were measured by ELISA according to the manufacturer's instructions using Human (GP73) ELISA Kit (Assay Kit Co. Ltd, Sunnyvale, California, USA). The kit uses a double-antibody sandwich ELISA to assay the level of human GP73.

The data collected were tabulated and analyzed by statistical package for the social sciences (SPSS, version 20; SPSS Inc., Chicago, Illinois, USA) software, on an IBM compatible computer. The results were expressed as range, mean ± SD. The χ2-test, the Mann–Whitney test, the t-test, analysis of variance (F) test, and the Kruskal–Wallis test were used for the analysis. P values of less than 0.05 were considered significant. Spearman's correlation was used for quantitative variables that were not normally distributed or when one of the variables was qualitative.


  Results Top


Sociodemographic characteristics of the studied groups are presented in [Table 1]. The mean age was 58.2 ± 7.8 years for HCC patients, 54.5 ± 10.2 years for CLD patients, and 52.9 ± 8.2 years for the control group. HCC was found more in men than in women and more in patients aged more than 50 years old with no statistically significant difference (P > 0.05).
Table 1: Sociodemographic characteristics of the studied groups

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The clinical data of group I (HCC group) are illustrated in [Figure 1]. About the etiology of cirrhosis; 70% was due to HCV, 5% was due to HBV, and 25% was due to other causes of cirrhosis. Regarding Barcelona Clinic Liver Cancer (BCLC) staging, HCC patients were BCLC A (45%) and BCLC B (37.5%) and BCLC C (17.5%).
Figure 1: Clinical data of group I (hepatocellular carcinoma group).

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Comparison was made among the three studied groups with respect to AFP, MDK, and GP73. [Table 2] shows that there was a highly significant difference (P< 0.001) between HCC and CLD groups and between HCC and control groups regarding AFP, MDK, and GP73. There was a highly significant difference (P< 0.001) between CLD and control groups regarding MDK and GP73, but there was no significant difference (P > 0.05) regarding AFP.
Table 2: Mean values of α-fetoprotein, Midkine, and Golgi protein 73 among the studied groups

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Relations study between AFP, MDK, GP73, and the other parameters in [Table 3] showed a nonsignificant difference between AFP, MDK, and GP73 serum levels and different types of BCLC, child classification, model for end-stage liver disease score, lymph node (LN) involvement, portal vein invasion, and tumor size. There was significant differences (P< 0.05) between BCLC A and BCLC B and also between BCLC A and BCLC C as regards GP73. The serum level of AFP increased from BCLC A to BCLC B and from Child A to Child B, but without statistically significant difference. Besides, the serum level of GP73 increased from BCLC A to BCLC B and from Child A to Child B but with no statistically significant difference.
Table 3: Relation between α-fetoprotein, Midkine, and Golgi protein 73 serum levels and different types of Barcelona Clinic Liver Cancer, child classification, model for end-stage liver disease score, and criteria of hepatocellular carcinoma group

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For the discrimination of the HCC group from the CLD patients, [Table 4] showed that at a cutoff value of 14.0 ng/ml, the sensitivity of AFP was 72.5%, specificity 77.8%, positive predictive value (PPV) 78.4%, and negative predictive value (NPV) 71.8%. The optimal diagnostic cutoff value for MDK based on the receiver operating characteristic (ROC) curve was 1585.0 pg/ml, with a sensitivity of 100% and specificity 88.9%, PPV 90.9%, and NPV 100%. The optimal diagnostic cutoff value for GP37 based on the ROC curve was 42.5 ng/ml giving a sensitivity of 90% and specificity of 83.3%, PPV of 85.7%, and NPV of 88.2%. The diagnostic efficacy of the biomarkers in detecting early-stage (BCLC 0-A) HCC, GP73, and MDK remained superior (0.941 and 0.869, respectively) to AFP (0.730), as shown in [Table 4] and [Figure 2].
Table 4: Evaluation of α-fetoprotein, Midkine, and Golgi protein 73 in the diagnosis of hepatocellular carcinoma and early hepatocellular carcinoma

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Figure 2: Receiver operating characteristic curve of α-fetoprotein, Midkine, and Golgi protein 73 for the diagnosis of early hepatocellular carcinoma showed that the cutoff point (point of highest sensitivity and specificity) was 17.6 ng/ml for α-fetoprotein, 3825 pg/ml for Midkine, and 84.5 ng/l for Golgi protein 73.

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  Discussion Top


In the current study, chronic HCV was the common one as the etiology of HCC representing 70% of cases, HBV was only 5%, and cirrhosis with unknown etiology was 25%. This is matched with Gómez Rodríguez et al.[11], in Spain, who found that HCV was the leading cause of liver disease. This also coincides with Amer et al.[12], who found that the major risk factor for cirrhosis and subsequent development of HCC in the Egyptian patient was chronic hepatitis C (67.7%) and to a lesser extent, chronic hepatitis B (8.8%) and coinfection with both viruses (4.8%), whereas Kumar et al.[13]in India found that chronic HBV infection was the major factor for the development of HCC in China.

AFP has been widely used as a serologic diagnostic tumor marker for HCC. However, serum AFP is elevated in only about 33–65% of small HCC and nonspecific elevation of serum AFP has been found in 15–58% of patients with chronic hepatitis and 11–47% of liver cirrhosis. Thus, there is a debate about the roles of AFP in early diagnosis and, particularly, surveillance of HCC[14]. Therefore, identification of new specific and sensitive biomarkers for early diagnosis is urgently needed[15].

MDK and GP73 were identified as important potential novel biomarkers for the diagnosis and early detection of HCCs[14].

In this study, we found a highly significant increase (P< 0.001) of the serum MDK level in patients with HCC (4313.4 ± 441.9 pg) compared with CLD patients (1166.7 ± 284.9 pg) and healthy controls (106.7 ± 25.6 pg). These results agreed with those of Shaheen et al.[1]in Cairo, Egypt, who reported that the mean values of the MDK levels in the HCC group were significantly higher when compared with the cirrhotic group (0.625 vs 0.15 ng/ml; P < 0.001) and to the healthy control group (0.625 vs 0.125 ng/ml; P < 0.001). Moreover, Vongsuvanh et al.[5], in Australia, reported that serum MDK was significantly higher in HCC (mean: 2.93 ng/ml) than in cirrhosis (mean: 0.88 ng/ml), CLD (mean: 0.65 ng/ml), and healthy control (mean: 0.70 ng/ml) (P< 0.0001 for all).

Regarding serum GP73 levels, statistical analysis has shown that there was a highly significant increase in GP73 mean values in HCC group (83.7 ± 16.03 ng/ml) in comparison with other groups and in CLD group (38.8 ± 7.2 ng/ml) in comparison with the control group (P< 0.0001 for all). These results were in agreement with Omran et al.[16], in Egypt, who have reported that GP73 was elevated in all patients with the HCC group (26.027 ± 12.26) showing the highest serum levels when compared with patients with cirrhosis (13.23 ± 7.97) and healthy controls with a statistically significant difference. El-Shafie et al.[17], in Egypt, also found that the serum level of GP73 was significantly higher in HCC cases (10.32 ± 2.46) than liver cirrhotic patient (3.79 ± 2.18). Moreover, El-Awady et al.[18], in Egypt, have reported that there were significantly higher GP73 levels in HCC group (11.77 ± 0.69) when compared with LC (2.7 ± 0.49) and control groups (0.40 ± 0.04). Moreover, the LC group showed significantly higher GP73 levels than the control group and Wang et al.[19] reported that serum GP73 in HCC was higher than in liver cirrhosis and chronic hepatitis and in all patients were higher than those in healthy individuals. On the other hand, Gu et al.[20], reported that GP73 was found to be elevated in patients with liver disease but did not distinguish between HCC, cirrhosis, and chronic hepatitis. Moreover, Ozkan et al.[21], in Turkey, and Shi et al.[22]said that there was no significant elevation of serum GP73 in HCC groups compared with that in liver cirrhosis groups and that the potential clinical value of GP73 as a better serum biomarker than AFP remains controversial.

The current study has shown that there was no significant correlation in the mean value of serum MDK with age and sex. This was in agreement with Saad et al.[2], who reported that the serum levels of MDK in patients with HCC were not correlated with age or sex.

This study has shown that there was no significant correlation in mean value of serum GP73 with age and sex. This was in agreement with Fouad et al.[23], Fathy et al.[24], in Egypt, and who reported that the serum levels of GP73 in patients with HCC were not correlated with age or sex.

An analysis of the present results have shown that there was no statistically significant differences between MDK and different BCLC stages of HCC, but its level increased with advanced BCLC stages. Vongsuvanh et al.[5], in Australia, have found that MDK was associated with the greatest number of aggressive clinical and tumor characteristics such as advanced BCLC stage (P = 0.006). On the other hand, Zhu et al.[14], in China, and Shaheen et al.[1], in Egypt, have reported that there was no association between serum MDK and BCLC stages.

Besides, this study has shown that there was high levels of GP73 with advanced Child–Pugh classification (P > 0.05). A similar result was obtained by El-Shafie et al.[17], who found a significant correlation between serum GP73 levels and child score in HCC patients. Dong et al.[25] and Sabry et al.[26], in Menoufia, Egypt, also, found that, in the HCC group, higher serum GP73 levels were significantly associated with higher Child–Pugh grade (P< 0.001). However, Mao et al.[27] reported that the serum level of GP73 in patients with HCC was not correlated with Child–Pugh grades (A, B, C).

In this study, there was an obvious elevation of the studied markers (AFP, MDK, and GP73) in HCC patients with LN involvement than those without LN involvement (1661.7 ± 3278.4 vs 478.2 ± 892.7, 4625.0 ± 567.9 vs 4257.9 ± 426.2 and 92.8 ± 2.5 vs 82.7 ± 16.6, respectively). Lu et al.[28], in China, reported that the high serum concentration of AFP was positively correlated with LN metastasis. Dong et al.[25] found that, in the HCC group, higher serum GP73 levels were significantly associated with regional LN metastasis (P = 0.011) and Sabry et al.[26], in Egypt, reported that there was a significant increase in mean values of serum GP73 in patients with HCC associated with LN enlargement.

In our study, the serum MDK had a greater area under the receiver operating characteristic curve (AUROC: 1.00) than AFP (0.855) suggesting that MDK is superior to AFP for HCC diagnosis. The optimal diagnostic cutoff for MDK based on the ROC curve was 1585 pg/ml with a sensitivity of 100% and specificity of 88.9% (PPV 90.9% and NPV 100%). This was in agreement with Zhu et al.[14], who reported that the AUROC curve of MDK (0.915) was found to be much larger than that of serum AFP (0.754) (P< 0.001). At the cutoff value of 0.654 ng/ml, the sensitivity of MDK for HCC diagnosis was 86.9%, which was much higher than that of AFP (51.9%). Moreover, Shaheen et al.[1], in Egypt, reported that the best cutoff values for MDK and AFP to discriminate HCC cases from those with liver cirrhosis were 0.387 and 88.5 ng/ml, respectively, with sensitivities (92.5 vs 40%), specificities (83.3 vs 96.7%), and accuracies (88.5 vs 68.2%), respectively. Then through the analysis of the ROC, the area under the curve of MDK (0.941) was found to be much larger than that of serum AFP (P< 0.001) with highly significant statistical difference. This means that the overall diagnostic performance of MDK for HCC diagnosis is much better than that of AFP. On the other hand, Vongsuvanh et al.[5] reported that AFP had a greater AUROC curve (AUROC 0.83) than MDK (0.70), suggesting that AFP is superior to MDK for HCC diagnosis. The optimal diagnostic cutoff for MDK based on the ROC curve was 0.44 ng/ml, with a sensitivity of 70.9% and specificity of 62.2% (PPV 48.0% and NPV 80.9%).

In this study, the serum GP73 level had a superior diagnostic performance to AFP in the detection of HCC (AUROC 0.952 with a sensitivity of 90% and specificity of 83.3% vs 0.855%; 72.5% and 77.8%, respectively). These results are in agreement with El-Awady et al.[18], who reported that, at the best cutoff value of 9.5 ng/ml, the sensitivity and specificity of GP73 in the selective diagnosis of HCC over liver cirrhosis, were 88.9 and 96%, respectively, with PPV (97%), NPV (85.7%), and an accuracy of 91.8% compared with an accuracy of 77% for the AFP. Similar results have been obtained by Allam et al.[29], who found that the best sensitivity and specificity of GP73 at cutoff value of more than 6 ng/ml was 92 and 87%, respectively, with a diagnostic accuracy of 89%. In disagreement with this result, Sangiovanni et al.[30], who reported that GP73 was surprisingly found to be decreased in HCC patients and expressed doubt on the diagnostic utility of GP73 as a serum marker of HCC and Gu et al.[20], who found that GP73 elevated in patients with liver disease but did not distinguish between HCC, cirrhosis, and chronic hepatitis.

The present study has shown that serum MDK may serve as a novel diagnostic tumor marker for the detection of early-stage HCC (BCLC 0/A), as MDK had a greater AUROC curve (0.869) than AFP (0.730). The optimal diagnostic cutoff for MDK based on the ROC curve was 0.3825 ng/ml, with a sensitivity of 88.9% and a specificity of 79.5% (PPV 50% and NPV 96.9%). This was in agreement with Zhu et al.[14], who reported that serum MDK had a better performance compared with AFP for distinguishing early-stage HCC from patients with liver cirrhosis. In detecting early-stage HCCs (BCLC 0/A), the sensitivity of MDK was much higher than that of AFP (87.1 vs 46.7%). The same findings were demonstrated by Shaheen et al.[1], who reported that in terms of early detection and diagnosis of HCC, MDK at a cutoff value of 0.387 ng/ml showed a superior diagnostic performance to differentiate early-stage HCC from patients with liver cirrhosis when compared with AFP at different cutoff values of 20, 88.5, and 200 ng/ml (BCLC 0/A; sensitivity, 90% vs 40, 20, and 0%, respectively) (P< 0.001). On the other hand, Vongsuvanh et al.[5] reported that in detecting early-stage (BCLC 0-A) HCC, AFP remained superior (0.79) to MDK (0.63).

In this study, it has been also observed that serum GP73 may serve as a novel diagnostic tumor marker for the detection of early HCC as the AUROC for GP73 was 0.941. The optimal diagnostic cutoff value for GP73 based on the ROC curve was 84.5 ng/ml with a sensitivity of 94.4% and specificity of 83.3%, PPV of 56.7%, NPV of 98.5%, and with an overall accuracy of 85.4%. This was in agreement with El-Shafie et al.[17], who demonstrated that the sensitivity and specificity of GP73 for HCC were superior to those of AFP, especially in early HCC, in their 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. Moreover, Ali et al.[31] reported that at the cutoff values of GP73 equivalent to 4.4 ng/ml, the accuracy for early diagnosis of HCC was 87%, and the sensitivity and specificity were 85 and 90%, respectively.


  Conclusion Top


Serum levels of MDK and GP73 are highly increased in HCC patients. MDK and GP73 have a better diagnostic performance than AFP for the detection of HCC in its early stage.

Finally, in addition to AFP, the measurement of serum MDK and GP73 can further improve the diagnosis of HCC, which is one of the most serious malignancies all over the world.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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Abstract
Introduction
Patients and Methods
Results
Discussion
Conclusion
References
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