| Citation: |
Huan Zhang, Xuezhong Lei. Research Advance in GP73 in the Clinical Diagnosis and Treatment of Patients with Chronic Hepatitis B[J]. Diseases & Research, 2022, 2(2): 53-56. DOI: 10.54457/DR.202202002
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Golgi protein 73 (GP73) is a type II integrative membrane protein located in the cellular Golgi apparatus. Research shows, that in addition to protein processing, GP73 is involved in cell differentiation, intercellular signaling and apoptosis. With the development of proteomics technology, the relationship between GP73 and chronic hepatitis B has been gradually revealed. In this review, the clinical diagnostic value and the therapeutic prediction of GP73 in chronic hepatitis B in recent years are reviewed, to provide ideas for the diagnosis and treatment of patients with chronic hepatitis B.
Golgi protein 73 (GP73) is a type II transmembrane glycoprotein found in the Golgi apparatus that is mainly expressed in epithelial cells of the colon, kidney, and prostate tissues, it is rarely or not expressed in muscle, lymphoid tissue, and white blood cells[1]. It was first measured by Kladney et al. in 2000 while studying the pathogenesis of adult giant cell hepatitis. In addition to protein processing, GP73 has been demonstrated to be involved in cell differentiation, intercellular signaling, and apoptosis[1]. Rosa[2] et al suggested that intrahepatic GP73 levels are closely related to serum GP73 levels, which implies that GP73 levels in the liver can be superior eflected in the blood. The expression level of serum GP73 in patients with good chronic hepatitis B is increased with high specificity and sensitivity[3], suggesting that serum GP73 can be considered as a new serological marker for liver disease detection. In the following, we review the recent research advances on GP73 and the clinical diagnosis and treatment of chronic hepatitis B, discuss the clinical value of serum GP73 in patients with chronic hepatitis B.
GP73 was first proposed to be associated with the progression of liver histopathological damage in chronic hepatitis B in 2005[4]. At the current stage, GP73 is gradually being recognized clinically as a serological marker to assist in the diagnosis of various diseases such as hepatocellular carcinoma and liver cirrhosis[5-7]. Hepatocellular carcinoma risk, metastasis, and prognosis are frequently evaluated using GP73 together with GDF-15, AFP, and aberrant prothrombin[8], as well as in conjunction with serological indicators including serum FFA, AFP-L3, PYGO2, and ALT, to monitor liver disease progression[9-11]. GP73 has even been reported as a noninvasive biomarker for nonalcoholic fatty liver disease[12,13]. GP73 is gradually being found to be an important guide for the diagnosis and prognosis of chronic hepatitis B. The combined test of GP73, AFP, and AFP-L3 exhibited a sensitivity of 81.08% and a specificity of 96.15% for the diagnosis of chronic hepatitis B, according to Jia's[10]study. Studies have revealed that the degree of liver fibrosis correlates favorably with the level of serum GP73 in individuals with chronic hepatitis B, and the rise in GP73 in vivo correlates positively with the disease's progression[14,15]. It's possible that aberrant activation, proliferation, and secretion mechanisms in liver cells result in significant amounts of GP73 being secreted into the Golgi apparatus, leading to an increase in GP73 levels in active hepatitis[16-18]. Serum GP73 concentration can be detected by ELISA kits, which are inexpensive, simple to operate, and have good promotion. That the detection of GP73 is more cost-effective.
GP73 can be used to predict the prognosis of individuals with viral and nonviral hepatitis, according to a study published in 2020 by Nikolaos[19] et al. In regard to determining whether a patient has active hepatitis B, some studies have shown that serum GP73 is more sensitive than traditional indicators such as ALT, and that when the threshold value reaches 124.76 ng/mL, the specificity of GP73 is higher, which can compensate for the deficiency caused by false-negative ALT in chronic hepatitis B virus carriers, but the efficacy of the two is better[20,21]. Elevated serum GP73 has also been demonstrated to be an independent risk factor for the development of liver inflammation[22], with a correlation coefficient of 0.524 with liver inflammatory activity, indicating that it could be a potential marker of hepatitis activity[23]. When the concentration reaches approximately 3650 ng/mL, the patient is at risk of developing cirrhosis or hepatocellular cancer[24]. GP73 levels should to be monitored regularly, if they gradually rise, clinicians should closely observe the progression of patients' liver disease and intervene in advance to reduce the risk of patients progressing to liver cancer and liver failure[25].
Although HBV virus replication is active in patients in this phase, the serum GP73 level in the body is normal in chronic hepatitis B immunological tolerance phase patients, who have not yet experienced liver inflammation[26]. Hepatic cell necrosis, prolonged hepatocellular inflammation, and the virus activating GP73 to promote its reproduction occur once HBV virus-infected individuals enter the immunological clearance phase, causing serum GP73 levels to keep rising[27]. Particularly, individuals with cirrhosis had considerably higher blood GP73 levels, indicating that the degree of hepatocyte necrosis is tightly correlated with serum GP73 levels[28]. In patients with chronic hepatitis B, the expression level of GP73, liver function, and fibrosis-related indexes increase with the increase in the inflammatory response. Enhancing liver function, fibrosis indexes, and GP73 testing in patients can detect liver inflammatory response early and help monitor hepatocellular damage promptly to determine prognosis[29]. Ma[30] et al. proposed that abdominal ultrasound combined with serum GP73 could improve the assessment of the degree of fibrosis in chronic hepatitis B. The two could complement each other and improve the assessment value. It has also been reported that serum GP73 can be used to diagnose the degree of fibrosis in nonantiviral patients with chronic hepatitis B[31,32], but this conclusion needs to be validated by further large sample studies.
Domestic GP73 studies mainly tend to focus on disease groups, such as chronic hepatitis B, cirrhosis, and primary liver cancer, and the serum GP73 levels of these diseases are significantly higher than those of healthy controls. The serum GP73 levels from high to low are the liver cancer group, cirrhosis group, chronic hepatitis B group, HBV carrier group, and healthy control group[33]. Several studies[23,34,35] reflect that serum GP73 cannot be used as a diagnostic marker for hepatocellular carcinoma, but can be used to determine the severity of liver fibrosis and cirrhosis, and suggest that there is no direct correlation between HBV infection and serum GP73 levels, and that HBV infection may not be the cause of elevated serum GP73 levels, but maybe the result of HBV infection that triggers liver inflammatory damage to upregulate GP73 expression, and there is no direct link with viral infection and replication levels. A recent foreign study, found that GP73 is not a reliable marker as a substitute for liver biopsy in the setting of low to moderate fibrosis and HAI (Histological Activity Index) classification[36]. It has been reported serum GP73 can only distinguish patients with liver cancer from the healthy population, but not liver fibrosis, cirrhosis and liver cancer[37]. However, the sample sizes of these studies are small, the findings are poorly supported, and the conclusions remain to be validated.
Although traditional serological markers such as ALT, AST, HBV-DNA, and PTA are now recognized to reflect the activity of liver inflammation to some extent, some studies report that 29.82% of patients with chronic hepatitis B still have active hepatitis without abnormal ALT manifestations, so liver biopsies performed in patients with chronic hepatitis B with normal ALT and elevated GP73 reveal significant hepatocyte damage (G2)[20]. However, many factors such as potential complications, sample size or sampling errors, and interobserver variability have hindered the widespread use of liver biopsy. Strict adherence to practice guidelines for chronic hepatitis B will deprive some patients with near-normal ALT of the opportunity to receive antiviral therapy[38]. In the follow-up management of chronic hepatitis B virus carriers, it was found that if GP73 levels are significantly elevated, patients are advised to initiate liver puncture biopsy or start antiviral therapy directly at this time, to avoid missing the timing when chronic hepatitis B virus carriers need antiviral therapy due to normal ALT[20]. A study conducted in 2015 by XU[39] et al examined the effect of ETV antiviral therapy for chronic hepatitis B patients with normal ALT and found that serum GP73 significantly reduced after three months of treatment. This could serve as a marker for monitoring the effectiveness of hepatitis treatment. The combination of GP73 and ALT has recently been proposed as a potential prognostic biomarker for predicting the outcome of antiviral therapy in chronic hepatitis B patients[40]. It has been reported that although serum GP73 diagnoses the severity of chronic hepatitis B independent of HBeAg quantification and HBV-DNA load, the effect of antiviral therapy and impaired liver function can still have an impact on it[3,34]. Dang[41] et al concluded that GP73 levels were higher in patients with HBeAg negative than in HBeAg positive patients, which is different from the findings of Cao and Cheng[32,42], considering that it may be caused by the problem of patient enrollment, and more clinical data are needed to prove it.
The predictive value of GP73 in hepatocellular carcinoma was initially demonstrated, and it is now known that GP73 can promote tumor cell proliferation, apoptosis, invasion, and migration through a variety of mechanisms, but the mechanism of action of GP73 in autophagy and chemoresistance is still poorly understood. It has been reported that exons have more advantages in detecting GP73[43], more extensive and in-depth studies and clinical trials are still needed to explore and thus develop new strategies for the early diagnosis and treatment of hepatocellular carcinoma. The studies related to the role of GP73 in the clinical diagnosis and treatment of slow hepatitis B are fewer and mostly small sample size studies, it is still controversial, especially for slow hepatitis B patients in the immune tolerance phase, which is still at the basic research stage. Whether GP73 has any guiding value and social value in the determination of antiviral efficacy and prediction of regression in immune tolerant patients with chronic hepatitis B is still at the preliminary stage of exploration, and more in-depth studies with larger samples of clinical data are needed. Or even multicenter randomized controlled trials. However, the association between the change in GP73 levels and the diagnosis and treatment of slow hepatitis B has been shown, and we believe that there will be more related studies exploring the value of GP73 in the diagnosis and treatment of slow hepatitis B, to provide ideas for the diagnosis and treatment of chronic hepatitis B patients.
ALB, albumin; ALT, alanine aminotransferase; AS, ascites; CHB, chronic hepatitis B; CI, confidence interval; CTP, Child–Turcotte–Pugh; EVB, esophageal variceal bleeding; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HE, hepatic encephalopathy; HR, hazard ratio; IQR, interquartile range.
The authors report no conflicts of interest in this work.
HZ make key contributions to research ideas or design, participate in the process of obtaining, analyzing and interpreting research data, draft or modify key content of the paper; XZL is responsible for directing the writing and finalizing of the article.
| [1] |
Kladneyrd, Bulla GA, Guo L, et al. GP73, a novel Golgi-localized protein upregulated by viral infection. Gene, 2000, 249(1/2): 53-65. DOI: 10.1016/S0378-1119(00)00136-0
|
| [2] |
Rosa FC, Chrustic C, Torres IL, et al. The small G protein Ar15 contributes to endosome-to-Golgi traffic by aiding the recruitment of the GARP complex to the Golgi. Biol Open, 2015, 4(4): 474-481. DOI: 10.1242/bio.201410975
|
| [3] |
Cao ZJ, Li ZQ, Wang H, et al. Algorithm of Golgi protein 73 and liver stiffness accurately diagnoses significant fibrosis in chronic HBV infection. Liver Int, 2017, 37(11): 1612-1621. DOI: 10.1111/liv.13536
|
| [4] |
Block TM, Comunale MA, Lowman M, et al. Use of targeted glycoproteomics to identify serum glycoproteins that correlate with liver cancer in woodchucks and humans. Proc Natl Acad Sci USA, 2005, 102(3): 779-784. DOI: 10.1073/pnas.0408928102
|
| [5] |
Nikolaos KG, Kalliopi Z, George G, et al. Serum Cartilage Oligomeric Matrix Protein and Golgi Protein-73: New Diagnostic and Predictive T ools for Liver Fibrosis and Hepatocellular Cancer? Cancers, 2021, 13(14): 3510. DOI: 10.3390/cancers13143510
|
| [6] |
Min D, Zhan HC, Xing L, et al. Serum Golgi protein 73 is a prognostic rather than diagnostic marker in hepatocellular carcinoma. Oncol lett, 2017, 14(5): 6277-6284. DOI: 10.3892/ol.2017.6938
|
| [7] |
Liang R, Liu ZY, Piao XM, et al. Research progress on GP73 in malignant tumors. Onco Targets Ther, 2018, 11: 7417-7421. DOI: 10.2147/OTT.S181239
|
| [8] |
Tian X. Study on the value of serum GDF-15, GP73 and AFP in the diagnosis of hepatocellular carcinoma. Lab Med Clin, 2021, 18(16): 2438-2440. DOI: 10.3969/j.issn.1672-9455.2021.16.040
|
| [9] |
Lin Z, Dang XJ, Hou ZH, et al. Study on the relationship between the changes of serum FFA and GP73 levels and the severity of chronic hepatitis B and its clinical significance. J Taishan Med College, 2018, 39(8): 921-923. DOI: 10.3969/j.issn.1004-7115.2018.08.035
|
| [10] |
Jia FY, Yu YH, Yu MJ, et al. Study on the changes and clinical value of serum AFP-L3, GP73, AFP in patients with chronic hepatitis B. Inter J Lab Med, 2020, 41(12): 1527-1529. DOI: 10.3969/j.issn.1673-4130.2020.12.029
|
| [11] |
Zheng ZH, Li WJ, Hui ZY, et al. Serological and virological response topegylated interferon α-2a and entecavir combination in patients with chronic hepatitis B. J Prac Hepato, 2021, 24(1): 19-22. DOI: 10.3969/j.issn.1672-5069.2021.01.006
|
| [12] |
Peng YM, Zeng Q, Wan LM, et al. GP73 is a TBC-domain Rab GTPase-activating protein contributing to the pathogenesis of non-alcoholic fatty liver disease without obesity. Nat Commun, 2021, 12(1): 1-16. DOI: 10.1038/s41467-020-20314-w
|
| [13] |
Wang LJ, Yao MJ, Liu SH, et al. Serum Golgi Protein 73 as a Potential Biomarker for Hepatic Necroinflammation in Population with Nonalcoholic Steatohepatitis. Dis Markers, 2020, 2020: 6036904. DOI: 10.1155/2020/6036904
|
| [14] |
Yao MJ, Wang LJ, Guan GW, et al. Value of serum Golgi protein 73 in assisting the diagnosis of moderate or severe liver injury in patients with chronic hepatitis B. J Clin Hepatol, 2018, 34(4): 755-759. DOI: 10.3969/j.issn.1001-5256.2018.04.012
|
| [15] |
Huang GH. Correlation of levels of serum GP73 and CTLA4 with degree of liver fibrosis in patients with chronic hepatitis B. Chin Pract Med, 2021, 48(14): 49-52. DOI: 10.3760/cma.j.cn115689-20210321-01138
|
| [16] |
Liu YP, Zhao Q, Ying Y, et al. A Study on Correlation Between Serum GP73, HA Levels and HBV DNA Load, Liver Function in Patients with Chronic Hepatitis B. Clin Misdiagn Misther, 2019, 32(9): 48-53. DOI: 10.3969/j.issn.1002-3429.2019.09.013
|
| [17] |
Deveci O, Kaplan I, Tekin R, et al. Prognostic value of golgiP 73 and beta 2-microglobulin in patients with viral hepatitis B. Acta Biochim Pol, 2020, 67(1): 131-134. DOI: 10.18388/abp.2020_5209
|
| [18] |
Ma LY, Zhen YN, Luo YP, et al. Expression and mechanism of gp73 in liver tissue of mouse liver fibrosis. Basic & Clin Med, 2020, 40(6): 771- 776.
|
| [19] |
Nikolaos KG, Tamás T, Zakera S, et al. Golgi protein-73: A biomarker for assessing cirrhosis and prognosis of liver disease patients. World J Gastroenterol, 2020, 26(34): 5130-5145. DOI: 10.3748/wjg.v26.i34.5130
|
| [20] |
Xu ZJ, Shen JK, Pan XN, et al. Predictive value of serum Golgi protein 73 for prominent hepatic necroinflfl ammation in chronic HBV infection. J Med Virol, 2018, 90(6): 1053-1062. DOI: 10.1002/jmv.25045
|
| [21] |
Yao MJ, Wang LJ, You H, et al. Serum GP73 combined AST and GGT reflects moderate to severe liver inflammation in chronic hepatitis B. Clin Chim Acta, 2019, 493: 92-97. DOI: 10.1016/j.cca.2019.02.019
|
| [22] |
Yang DL, Yao MJ, Yan Y, et al. Deoxycholic Acid Upregulates Serum Golgi Protein 73 through Activating NF-κB Pathway and Destroying Golgi Structure in Liver Disease. Biomolecules, 2021, 11(2): 205. DOI: 10.3390/biom11020205
|
| [23] |
Lu FM, Zeng WJ, Wen XJ, et al. New markers related to antiviral therapy of chronic hepatitis B and their clinical application. Chin Hepatol, 2019, 24(5): 483-486. DOI: 10.3969/j.issn.1008-1704.2019.05.001
|
| [24] |
Xu ZJ, Pan XN, Wei MJ, et al. Correlation between serum GP73 level and IL-6 content in patients with chronic HBV infection. Chin Hepatol, 2017, 22(2): 136-139. DOI: 10.3969/j.issn.1008-1704.2017.02.014
|
| [25] |
Liu QY, Chang Y, Zhang W, et al. Prediction of cirrhosis progression by GP73 in patients with chronic hepatitis B. Med J Chin People's Armed Police Forces, 2020, 31(4): 317-323. DOI: 10.3969/j.issn.1004-3594.2020.04.011
|
| [26] |
Xu ZJ, Pan XN, Wei MJ, et al. Changes of serum GP73 before and after entecavir antiviral treatment in patients with chronic hepatitis B. Chin J Exp Clin Infect Dis (Electronic Edition), 2016, 10(3): 298-303. DOI: 10.3877/cma.j.issn.1674-1358.2016.03.010
|
| [27] |
Liu L, Zhu JY, Yang J. GP73 facilitates hepatitis B virus replication by repressing the NF-κB signaling pathway. J Med Virol, 2020 Feb 20.
|
| [28] |
Luo SY, He Y. Influencing Factors of Liver Inflammation and Fibrosis in Patients with Chronic Hepatitis B and Its Correlation with Serum Golgi Protein 73. Med Inf, 2021, 34(15): 5-8. DOI: 10.3969/j.issn.1006-1959.2021.15.002
|
| [29] |
Jiang N, Li Y, Wang GD, et al. Detection of hepatic function, fibrosis index and expression of GP73 in chronic hepatitis B patients with different inflammation grades. Hainan Med J, 2019, 30(24): 3155-3158. DOI: 10.3969/j.issn.1003-6350.2019.24.007
|
| [30] |
Ma SH, Liu WY, Chen C, et al. Value of serum GP73 combined with abdominal ultrasonography in evaluating the degree of liver fibrosis in CHB. Shandong Med J, 2022, 62(1): 25-29. DOI: 10.3969/j.issn.1002-266X.2022.01.006
|
| [31] |
Fang X, Shan S, Liu LW, et al. Serum Golgi glycoprotein 73 is superior to APRI and FIB-4 in the diagnosis of significant fibrosis in patients with chronic HBV infection. Mod Dig Intervention, 2020, 25(4): 529-532. DOI: 10.3969/j.issn.1672-2159.2020.04.027
|
| [32] |
Cao Z, Li Z, Wang Y, et al. Assessment of serum Golgi protein 73 as a biomarker for the diagnosis of significant fibrosis in patients with chronic HBV infection. J Viral Hepat, 2017, 1: 57-65. DOI: 10.1111/jvh.12786
|
| [33] |
Yuan JL, Huang H, Cheng Q. Application of serum prealbumin combined with golgi protein 73 in the detection and treatment of liver disease. Chin Community Doctors, 2017, 33(3): 108-109. DOI: 10.3969/j.issn.1007-614x.2017.3.63
|
| [34] |
Liu TH, Yao MJ, Liu SH, et al. Serum Golgi protein 73 is not a suitable diagnostic marker for hepatocellular carcinoma. Oncotarget, 2017, 8(10): 16498-16506. DOI: 10.18632/oncotarget.14954
|
| [35] |
Yao MJ, Wang LJ, Leung PSC, et al. The clinical signifificance of GP73 in immunologically mediated chronic liver diseases: experimental data and literature review. Clin Rev Allergy Immunol, 2018, 54(2): 282-294. DOI: 10.1007/s12016-017-8655-y
|
| [36] |
Aynur A, Mehmet H T, Zülay K, et al. GP73 level in patients with chronic hepatitis B: Relationship with liver biopsy, levels of ALT, AST and HBV DNA. Indian J Pathol &Microbiol, 2022, 65(1): 55-58. DOI: 10.4103/IJPM.IJPM_1149_20
|
| [37] |
Liu YN, Yao MJ, Zheng SJ, et al. Clinical application of serum Golgi protein 73 in patients with chronic liver diseases. Chin J Hepatol, 2022, 30(2): 4-8. DOI: 10.3760/cma.j.cn501113-20210210-00084
|
| [38] |
Zhang XK, SiTu RR. Clinical value of combined detection of alpha?fetoprotein, alpha?fetoprotein alloplasm?3 ratio and Golgi so? ma protein 73 in primary liver cancer. J Pract Med, 2021, 37(8): 1068-1071. DOI: 10.3969/j.issn.1006⁃5725.2021.08.021
|
| [39] |
Xu ZJ, Liu LG, Pan XN, et al. Serum Golgi Protein 73 (GP73) is a Diagnostic and Prognostic Marker of Chronic HBV Liver Disease. Medicine (Baltimore), 2015, 94(12): e659. DOI: 10.1097/MD.0000000000000659
|
| [40] |
Wei MY, Xu ZJ, Pan XN, et al. Serum GP73-An additional biochemical marker for liver inflflammation in chronic HBV infected patients with normal or slightly raised ALT. Sci Rep, 2019, 9(1): 1170-1176. DOI: 10.1038/s41598-018-36480-3
|
| [41] |
Dang YN, Jia ST, Zhao W, et al. Correlation Analysis of Serum IL-17A and GP73 Levels with Liver Function Indexes and Disease Severity in Patients with Chronic Hepatitis B. Prog Mod Biomed, 2020, 20(23): 4580-4584. DOI: 10.13241/j.cnki.pmb.2020.23.039
|
| [42] |
Cheng H, Ju H, Song DS, et al. Value of serum angiopoietin-like protein 2 and Golgi protein 73 levels in the diagnosis of hepatic fi-brosis in patient with chronic hepatitis B. J Pract Hepatol, 2019, 22(4): 494-497.
|
| [43] |
Xia YY, Zhang YY, Shen MJ, et al. Golgi protein 73 and its diagnostic value in liver diseases. Cell Prolif, 2019, 52(2): e12538. DOI: 10.1111/cpr.12538
|
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