Clinical Reviews in Allergy & Immunology

, Volume 54, Issue 2, pp 282–294 | Cite as

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

  • Mingjie Yao
  • Leijie Wang
  • Patrick S. C. Leung
  • Yanmei Li
  • Shuhong Liu
  • Lu Wang
  • Xiaodong Guo
  • Guangde Zhou
  • Ying Yan
  • Guiwen Guan
  • Xiangmei Chen
  • Christopher L. Bowlus
  • Tianhui Liu
  • Jidong Jia
  • M. Eric Gershwin
  • Xiong Ma
  • Jingmin Zhao
  • Fengmin Lu
Article

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.

Keywords

Fibrosis Chronic liver disease Liver stiffness FIB-4 APRI 

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

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12016_2017_8655_Fig6_ESM.gif (14 kb)

High-resolution image (GIF 13 kb)

12016_2017_8655_MOESM1_ESM.tiff (97 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)
12016_2017_8655_Fig7_ESM.gif (19 kb)

High-resolution image (GIF 19 kb)

12016_2017_8655_MOESM2_ESM.tiff (9.3 mb)
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)
12016_2017_8655_Fig8_ESM.gif (27 kb)

High-resolution image (GIF 26 kb)

12016_2017_8655_MOESM3_ESM.tiff (178 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)
12016_2017_8655_MOESM4_ESM.doc (64 kb)
Supplementary Table 1 (DOC 64 kb)
12016_2017_8655_MOESM5_ESM.doc (58 kb)
Supplementary Table 2 (DOC 57 kb)
12016_2017_8655_MOESM6_ESM.doc (68 kb)
Supplementary Table 3 (DOC 67 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  • Mingjie Yao
    • 1
  • Leijie Wang
    • 1
  • Patrick S. C. Leung
    • 2
  • Yanmei Li
    • 3
  • Shuhong Liu
    • 4
  • Lu Wang
    • 1
  • Xiaodong Guo
    • 4
  • Guangde Zhou
    • 4
  • Ying Yan
    • 1
  • Guiwen Guan
    • 1
  • Xiangmei Chen
    • 1
  • Christopher L. Bowlus
    • 5
  • Tianhui Liu
    • 6
  • Jidong Jia
    • 6
  • M. Eric Gershwin
    • 2
  • Xiong Ma
    • 3
  • Jingmin Zhao
    • 4
  • Fengmin Lu
    • 1
  1. 1.Department of Microbiology & Infectious Disease Center, School of Basic Medical SciencesPeking University Health Science CenterBeijingPeople’s Republic of China
  2. 2.Division of Rheumatology/Allergy and Clinical Immunology, School of MedicineThe University of CaliforniaDavisUSA
  3. 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 DiseaseShanghaiPeople’s Republic of China
  4. 4.Department of Pathology and HepatologyBeijing 302 HospitalBeijingPeople’s Republic of China
  5. 5.Division of Gastroenterology and Hepatology, School of MedicineThe University of CaliforniaDavisUSA
  6. 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 DiseasesBeijingPeople’s Republic of China

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