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The Clinical Significance of GP73 in Immunologically Mediated Chronic Liver Diseases: Experimental Data and Literature Review

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Abstract

There is significant void in establishing validated non-invasive surrogate biomarkers of liver fibrosis/cirrhosis in chronic liver diseases (CLD). Golgi protein 73 (GP73) has been suggested as a potential serum marker for the diagnosis of hepatocellular carcinoma (HCC). However, significant background of cirrhosis could have accounted for the elevation of serum GP73 in HCC. In this study, we have taken advantage of a well-defined extensive cohort of 3044 patients with either compensated cirrhosis (n = 1247), decompensated cirrhosis (n = 841) or pre-cirrhotic CLD (n = 956) and our ability to quantify serum GP73 to define the potential of serum GP73 as a biomarker of liver cirrhosis/fibrosis in CLD. The diagnostic value of GP73 was compared with aspartate aminotransferase-to-platelet ratio index (APRI), fibrosis index based on four factors (FIB-4) and liver stiffness measurement (LSM). Immunohistochemical analysis was performed to measure hepatic GP73 expression. Receiver operating characteristic curve analysis demonstrated that serum GP73 had a good diagnostic potential for compensated cirrhosis regardless of etiology. The diagnostic performance of GP73 is better than APRI, FIB-4 and similar with LSM, especially in patients with severe inflammation, steatosis and cholestasis. Notably, in patients of autoimmune liver diseases, non-alcoholic fatty liver disease and viral hepatitis, serum GP73 also exhibited diagnostic value for advanced fibrosis as well as cirrhosis. Furthermore, there is also a gradual increase in GP73 expression with disease progression from mild fibrosis to cirrhosis. In conclusion, GP73 is an effective and reliable serological marker for the diagnosis of advanced fibrosis and prediction of appearance of cirrhosis.

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Abbreviations

GP73:

Golgi protein 73

HCC:

hepatocellular carcinoma

ALT:

alanine aminotransferase

AST:

aspartate aminotransferase

ALP:

alkaline phosphatase

GGT:

gamma glutamyl transpeptidase

TBA:

total bile acid

ALB:

albumin

PA:

prealbumin

qPCR:

quantitative real-time PCR

PLT:

platelet count

IQR:

interquartile range

APRI:

AST-to-platelet ratio index

FIB-4:

fibrosis index based on four factors

LSM:

liver stiffness measurement

AILDs:

autoimmune liver diseases

NAFLD:

non-alcoholic fatty liver disease

CLD:

chronic liver diseases

HBV:

hepatitis B virus

CHB:

chronic hepatitis B

HBsAg:

hepatitis B surface antigen

HCV:

hepatitis C virus

CHC:

chronic hepatitis C

H & E:

hematoxylin and eosin

HRP:

horseradish peroxidase

ROC:

receiver operating characteristic curve

AUC:

the area under the receiver operating characteristic curve

PPV:

positive predictive value

NPV:

negative predictive value

BMI:

Body Mass Index

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Funding

This work was supported by the National S&T Major Project for Infectious Diseases (No. 2017ZX10302201 and 2017ZX10202203), the project from Beijing Municipal Science and Technology Commission (Z161100000116047 and D161100002716003), the National Natural Science Foundation of China Grant (No. 81372603, 81471938, 81325002 and 81620108002), the 111 Project (B07001), Research Fund of the Capital Medical Development (Grant No. 2014-2-5032) and the project from the Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (code XMLX201606).

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Author notes

  1. Mingjie Yao, Leijie Wang, Patrick S. C. Leung and Yanmei Li contributed equally to this work.

Authors and Affiliations

  1. Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, 100191, Beijing, People’s Republic of China

    Mingjie Yao, Leijie Wang, Lu Wang, Ying Yan, Guiwen Guan, Xiangmei Chen & Fengmin Lu

  2. Division of Rheumatology/Allergy and Clinical Immunology, School of Medicine, The University of California, Davis, CA, 95616, USA

    Patrick S. C. Leung & M. Eric Gershwin

  3. State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, 200001, Shanghai, People’s Republic of China

    Yanmei Li & Xiong Ma

  4. Department of Pathology and Hepatology, Beijing 302 Hospital, 100039, Beijing, People’s Republic of China

    Shuhong Liu, Xiaodong Guo, Guangde Zhou & Jingmin Zhao

  5. Division of Gastroenterology and Hepatology, School of Medicine, The University of California, Davis, CA, 95616, USA

    Christopher L. Bowlus

  6. Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Diseases, 100050, Beijing, People’s Republic of China

    Tianhui Liu & Jidong Jia

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  1. Mingjie Yao
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  2. Leijie Wang
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Corresponding authors

Correspondence to Patrick S. C. Leung, Xiong Ma, Jingmin Zhao or Fengmin Lu.

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Electronic Supplementary Material

High-resolution image (GIF 13 kb)

Supplementary Figure 1

The serum levels of GP73 in different patient populations. HC: healthy controls; CLC: compensated cirrhosis; DLC: decompensated cirrhosis. ***p value < 0.001 based on differences between medians with the Mann–Whitney U test. (TIFF 96 kb)

High-resolution image (GIF 19 kb)

Supplementary Figure 2

Immunohistochemistry of GP73 protein in different stages of fibrotic liver tissues (×400); CHB (a), AILDs (b) and NAFLD (c). (TIFF 9559 kb)

High-resolution image (GIF 26 kb)

Supplementary Figure 3

Expression of GP73 can be induced by IL-6 and STAT3C. (a) Quantitative real-time PCR detection of mRNA level of GP73 and furin in huh7 cells after stimulation with 25 ng/mL IL-6 for 2 h. (b) Quantitative real-time PCR detection of mRNA of GP73 and furin in huh7 cells after transient-transfected STAT3C after 48 h. (c) Dual-luciferase assay in huh7 indicates that STAT3C activates the GP73 promoter. The experiments were repeated at least twice. (TIFF 178 kb)

Supplementary Table 1

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Supplementary Table 2

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Supplementary Table 3

(DOC 67 kb)

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Yao, M., Wang, L., Leung, P.S.C. et al. The Clinical Significance of GP73 in Immunologically Mediated Chronic Liver Diseases: Experimental Data and Literature Review. Clinic Rev Allerg Immunol 54, 282–294 (2018). https://doi.org/10.1007/s12016-017-8655-y

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