Serum GP73 combined AST and GGT reflects moderate to severe liver inflammation in chronic hepatitis B

doi:10.1016/j.cca.2019.02.019

Clinica Chimica Acta

Volume 493, June 2019, Pages 92-97

https://doi.org/10.1016/j.cca.2019.02.019 Get rights and content

Highlights

•
Hepatic inflammation model (HIM) is a novel model based on GP73, AST, GGT.
•
HIM performed excellent diagnostic value in chronic hepatitis B patients (CHB).
•
HIM maintained good diagnostic value in CHB patients with no elevated ALT.
•
GP73 was an important source of the diagnostic value improvement for HIM.

Abstract

Background

Non-invasive method to identify chronic hepatitis B (CHB) patients with at least moderate inflammatory lesion but no increased ALT is an unmet need.

We evaluated Golgi protein 73 (GP73) based hepatic inflammation model (HIM) as a serum surrogate for liver necroinflammatory activity, especially in those with ALT less than traditional upper concentration.

Methods

The diagnostic performances of HIM were evaluated in 2 independent cohorts of liver biopsy proved CHB patients by receiver operating characteristic (ROC) curve analysis.

Results

HIM, a suggested index combined GP73, gamma-glutamyltransferase and AST, could significantly improve the diagnostic accuracy for liver necroinflammation (Area under ROC, AUROC: 0.890). More importantly, HIM still exhibit excellent diagnostic value (AUROC: 0.873) to identify patients with at least moderate liver necroinflammatory activity but with ALT <40 U/l. Serum GP73 was the major source of improvement for diagnostic model's accuracy.

Conclusion

HIM is probably a promising non-invasive index to identify CHB patients with moderate to severe liver necroinflammation, especially in those with ALT <40 U/l.

Introduction

Chronic hepatitis B virus (HBV) infection is a worldwide health problem, which can lead to liver fibrosis, cirrhosis, liver failure and hepatocellular carcinoma (HCC) [1]. Longitudinal studies indicated that patients with liver necroinflammatory activation and/or fibrosis are at increased risk of end stage liver diseases including HCC. Fortunately, timely antiviral treatment could slow down or even reverse the progression of chronic liver disease and prevent occurrence of end-stage liver disease [[2], [3], [4]]. Thus, liver necroinflammation and/or fibrosis have been recommended critical indications for timely antiviral treatment [5,6], Currently, aberrant elevation of alanine transaminase (ALT) activity is an important laboratory indication to initiate antiviral treatment. However, as previously reported, about 13.8% to 47.5% HBsAg positive individuals underwent constantly liver damage but with normal ALT [[7], [8], [9], [10], [11]]. Though histological evaluation is a “golden standard” for liver damage diagnosis, only people who meet the standards were recommended for liver biopsy [12]. Therefore, additional non-invasive biomarkers are needed to identify individuals who have active liver necroinflammation among those chronic HBV infected population.

GP73 is a 73 kD protein located in Golgi membrane, which can be sliced by proprotein convertase furin to release into blood. Increased serum GP73 has been suggested as a surrogate biomarker for liver fibrosis and cirrhosis [[13], [14], [15], [16]]. Increased GP73 was also observed in liver inflammation, which is the major cause of liver fibrosis [[17], [18], [19]]. Therefore, it is worthwhile to explore the diagnostic potential of GP73 based diagnostic model for liver necroinflammatory lesion in patients with chronic hepatitis B.

In this study, several GP73 based models were established to optimize the diagnostic accuracy for moderate liver necroinflammation. Among these models, the model which combined GP73, aspartate aminotransferase (AST) and gamma glutamyltransferase (GGT) was defined as the hepatic inflammation model (HIM) to reflect the presence of moderate liver necroinflammation. Then, serum GP73, the major source of improvement for diagnostic model's accuracy, has been further explored in outpatients with chronic hepatitis B infection, and its relationship between liver necroinflammation was then confirmed from various aspects.

Section snippets

Clinical characteristics of patients

This study included two independent cohorts. The first retrospective cohort was composed of the outpatients from 2010 to 2014 from 302 Military Hospital, Beijing, China. All patients had laboratory evidences of chronic HBV infection (HBsAg and/or HBV DNA positive for at least 6 months) and had stored serum available. None of them received anti-viral treatment in the past 6 months. All of participants had accepted liver biopsy to verify liver disease progression. Following indexes including

Clinical characteristics of the patients

As shown in Table 1, the 302 Military Hospital of China cohort composed of 367 treatment naïve individuals with laboratory evidence of chronic hepatitis B infection. In addition, 82 patients with significant liver fibrosis containing 39 longitudinal patients from the Friendship hospital and 121 healthy volunteers were enrolled.

Construction of novel models for the assessment of liver necroinflammation

By using Spearman test, the correlation between necroinflammatory activity and common clinical indexes was explored (Table 2). And subsequent multivariate analysis

Discussion

Liver histological lesion is widely accepted as an important indication for chronic HBV infected individuals to receive anti-viral treatment. To identify these patients, non-invasive serum biomarkers with power to identify whether an individual suffering moderate liver injury is urgently needed, especially in those CHB patients with no increased ALT. Previously, some studies have also established diagnostic models to predict inflammation. However, most of them based on four or more clinical

Acknowledgements

The authors thank Professor Anna S. Lok for critical suggestions of the manuscript. This work was supported by the National Science and Technology Major Project for Infectious Diseases (China, No. 2017ZX10201201, 2017ZX10202202, 2017ZX10202203 and 2017ZX10302201), Beijing Municipal Science & Technology Commission (China, No. Z161100000116047) and China Postdoctoral Science Foundation (No. 2017M620544 and 2018T110014). The funders had no role in study design, data collection and analysis,

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With increasingly prevalent coexistence of chronic hepatitis B (CHB) and hepatic steatosis (HS), simple, non-invasive diagnostic methods to accurately assess the severity of hepatic inflammation are needed. We aimed to build a machine learning (ML) based model to detect hepatic inflammation in patients with CHB and concurrent HS.
We conducted a multicenter, retrospective cohort study in China. Treatment-naive CHB patients with biopsy-proven HS between April 2004 and September 2022 were included. The optimal features for model development were selected by SHapley Additive explanations, and an ML algorithm with the best accuracy to diagnose moderate to severe hepatic inflammation (Scheuer's system ≥ G3) was determined and assessed by decision curve analysis (DCA) and calibration curve. This study is registered with ClinicalTrials.gov (NCT05766449).
From a pool of 1,787 treatment-naive patients with CHB and HS across eleven hospitals, 689 patients from nine of these hospitals were chosen for the development of the diagnostic model. The remaining two hospitals contributed to two independent external validation cohorts, comprising 509 patients in validation cohort 1 and 589 in validation cohort 2. Eleven features regarding inflammation, hepatic and metabolic functions were identified. The gradient boosting classifier (GBC) model showed the best performance in predicting moderate to severe hepatic inflammation, with an area under the receiver operating characteristic curve (AUROC) of 0.86 (95% CI 0.83–0.88) in the training cohort, and 0.89 (95% CI 0.86–0.92), 0.76 (95% CI 0.73–0.80) in the first and second external validation cohorts, respectively. A publicly accessible web tool was generated for the model.
Using simple parameters, the GBC model predicted hepatic inflammation in CHB patients with concurrent HS. It holds promise for guiding clinical management and improving patient outcomes.
This research was supported by the National Natural Science Foundation of China (No. 82170609, 81970545), Natural Science Foundation of Shandong Province (Major Project) (No. ZR2020KH006), Natural Science Foundation of Jiangsu Province (No.BK20231118), Tianjin Key Medical Discipline (Specialty), Construction Project, TJYXZDXK-059B, Tianjin Health Science and Technology Project key discipline special, TJWJ2022XK034, and Research project of Chinese traditional medicine and Chinese traditional medicine combined with Western medicine of Tianjin municipal health and Family Planning Commission (2021022).
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Citation Excerpt :
The serum hepatitis B core antibody was a strong indicator for assessing the hepatic inflammatory degree and was used for antiviral treatment decisions in CHB patients with normal ALT levels.21 Serum Golgi protein 73 (GP73) combined with AST and GGT reflected moderate to severe liver inflammation in patients with CHB.22 Furthermore, a logistic regression model established based on biochemical parameters could be used to effectively assess liver necroinflammation in patients with CHB who have normal or minimally elevated ALT levels.23
Effective hepatic blood flow (EHBF) decreases with liver disease progression, and identifying liver pathology is critical for patients with liver disease. This study was designed to elucidate the correlation between EHBF and liver pathology and explore the potential of EHBF for predicting the degree of liver pathology.
In this study, 207 patients with hepatitis B virus (HBV) who underwent liver biopsy and indocyanine green (ICG) clearance tests were enrolled. EHBF was measured using the ICG clearance test, and liver tissue was histologically analyzed to determine the pathological stage according to the Scheuer scoring system. Demographic data, biochemical indexes, and FibroScan data were collected for statistical analysis.
EHBF levels decreased as the liver histological stages of inflammation and fibrosis increased (P < 0.01). EHBF was significantly negatively associated with the levels of alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, alkaline phosphatase, aspartate aminotransferase-to-platelet ratio index, fibrosis index based on the four factors, and liver stiffness measurement (P < 0.05). The EHBF levels of patients without liver inflammation (G0) were significantly higher than those of patients with liver inflammation (G1–4) (P < 0.001). The area under the receiver operating characteristic curve (AUROC) value for discriminating patients without liver inflammation was 0.827, and the optimal cutoff value was 0.936 L/min. The EHBF levels of patients with severe liver inflammation (G4) were significantly lower than those of patients with G0–3 liver inflammation (P < 0.001). The AUROC value for discriminating patients with severe liver inflammation was 0.792, and the optimal cutoff value was 0.552 L/min. The EHBF levels of patients without liver fibrosis (S0) were significantly higher than those of patients with liver fibrosis (S1–4) (P < 0.001). The AUROC value for discriminating patients without liver fibrosis was 0.633, and the optimal cutoff value was 1.173 L/min. The EHBF levels of patients with liver cirrhosis (S4) were significantly lower than those of patients with S0–3 liver fibrosis (P < 0.001). The AUROC value for discriminating patients with liver cirrhosis (S4) was 0.630, and the optimal cutoff value was 0.562 L/min.
EHBF levels and liver pathology are significantly correlated. EHBF could effectively reflect liver inflammation and fibrosis in patients infected with HBV, especially for patients without liver inflammation or liver fibrosis.
Validation of the novel GLAS algorithm as an aid in the detection of liver fibrosis and cirrhosis based on GP73, LG2m, age, and sex
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View all citing articles on Scopus

¹: Mingjie Yao, Leijie Wang, Hong You contributed equally to this study.

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Serum GP73 combined AST and GGT reflects moderate to severe liver inflammation in chronic hepatitis B

Highlights

Abstract

Background

Methods

Results

Conclusion

Introduction

Section snippets

Clinical characteristics of patients

Clinical characteristics of the patients

Construction of novel models for the assessment of liver necroinflammation

Discussion

Acknowledgements

Lancet

Gastroenterology

J. Hepatol.

Clin. Biochem.

Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures

J. Viral Hepat.

Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B

Hepatology

EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection

J. Hepatol.

AASLD guidelines for treatment of chronic hepatitis B

Hepatology

High prevalence of significant liver fibrosis and cirrhosis in chronic hepatitis B patients with normal ALT in central Europe

J. Med. Virol.

Histologic disease in patients with chronic hepatitis B, high HBV DNA, and Normal alanine aminotransferase concentrations

Curr. Hepatitis Rep.

Should chronic HBV infected patients with normal ALT treated: debate

Hepatol. Int.