Editor's Note: Chronic hepatitis B (CHB) is a major cause of liver fibrosis, affecting over 257 million people worldwide. If not detected and treated early, early fibrosis may progress to cirrhosis, greatly increasing the risk of hepatocellular carcinoma (HCC). It is estimated that nearly one million deaths each year are related to CHB.Liver biopsy is the “gold standard” for diagnosing liver fibrosis, but due to its high cost, invasive nature, and other disadvantages, it is not widely used. Currently, various non-invasive tests (NITs) based on serum biochemical indicators and/or imaging have been developed to evaluate liver stiffness and diagnose liver fibrosis, aiming to identify high-risk populations early for timely intervention and management. However, the diagnostic performance of various NITs varies, and some diagnostic devices are not easily accessible. Finding an NIT with high accuracy and accessibility is a clinical challenge.
On June 7, 2024, at the European Association for the Study of the Liver (EASL) Annual Meeting in Milan, Italy, a team led by Professor Jie Li from the Nanjing Drum Tower Hospital, in collaboration with Professor Julie Zhu from Suzhou Fifth People’s Hospital and Professor Minghua Zheng from the First Affiliated Hospital of Wenzhou Medical University, shared a new non-invasive diagnostic method for CHB-related liver fibrosis (Abstract Number: FRI-022).
Research Background
N-terminal propeptide of type III collagen (PRO-C3) is a direct marker of liver fibrosis, released into the blood during the formation of type III collagen in the liver fibrosis process. Golgi protein 73 (GP73) is a transmembrane glycoprotein located in the Golgi apparatus, primarily expressed in bile duct epithelial cells in normal individuals, with low expression in hepatocytes. Previous studies have shown that both markers can be used to assess fibrosis progression in various chronic liver diseases. However, the diagnostic performance of PRO-C3 and GP73 in CHB-related liver fibrosis is not yet clear.
Research Methods
The study included treatment-naive CHB patients who underwent liver histological examination and serum testing between October 15, 2017, and December 30, 2021, at Nanjing Drum Tower Hospital and Suzhou Fifth People’s Hospital. Liver fibrosis was assessed using the Scheuer scoring system (S0-S4), with S2-4 defined as significant fibrosis and S3-4 as advanced fibrosis. Serum PRO-C3 and GP73 levels were measured using enzyme-linked immunosorbent assay (ELISA). The diagnostic value of six non-invasive scores (PRO-C3, GP73, combined PRO-C3 and GP73, liver stiffness measurement (LSM), FIB-4, and APRI) in identifying CHB-related significant and advanced fibrosis was evaluated using receiver operating characteristic (ROC) curves and the DeLong test.
Research Results
The study included 324 patients (median age 39, 63.5% male), with 167 (51.5%) having S2-4 fibrosis and 83 (25.6%) having S3-4 fibrosis. Among them, 167 patients underwent transient elastography.
Results showed that PRO-C3 and GP73 levels were significantly higher in patients with S2-4 and S3-4 fibrosis compared to those with S0-1 and S0-2 fibrosis (P<0.001). Multivariate logistic regression analysis showed that after adjusting for sex, age, body mass index, liver enzymes, and HBV DNA levels, PRO-C3 was an independent predictor of significant fibrosis (OR=1.04, 95% CI: 1.03-1.06) and advanced fibrosis (OR=1.04, 95% CI: 1.03-1.05). The area under the ROC curve (AUC) for PRO-C3 and GP73 in diagnosing significant fibrosis were 0.81 (0.74-0.87) and 0.75 (0.68-0.82), respectively, and for advanced fibrosis, 0.80 (0.73-0.86) and 0.73 (0.66-0.80), respectively.
When PRO-C3 and GP73 were used together, the AUC for diagnosing significant fibrosis was 0.84 (0.77-0.89), which, while not significantly different from PRO-C3 alone, was significantly higher than FIB-4 [0.64 (0.56-0.71), P<0.001], APRI [0.72 (0.64-0.78), P=0.02], LSM [0.74 (0.67-0.81), P=0.049], and GP73 alone (P=0.02). For advanced fibrosis, the diagnostic performance of PRO-C3 and the combined PRO-C3 and GP73 was superior to FIB-4 and comparable to LSM and APRI.
Research Conclusion
PRO-C3, especially when combined with GP73, is a reliable non-invasive marker for identifying liver fibrosis in CHB patients, with diagnostic accuracy comparable to LSM. This provides a new, cost-effective, and accurate option for monitoring fibrosis progression and guiding clinical decisions in CHB patients.
Researchers’ Insights
Our study shows that PRO-C3 and GP73 levels are significantly elevated in CHB-related fibrosis patients and that these markers have good efficacy in diagnosing liver fibrosis in CHB patients. For diagnosing significant fibrosis, PRO-C3 alone is superior to FIB-4 and comparable to LSM. When combined with GP73, its diagnostic performance further improves, significantly surpassing FIB-4, APRI, and LSM.
Previous literature has reported the relationship between PRO-C3 and liver fibrosis in MASLD patients, which is consistent with our findings on PRO-C3 and significant and advanced fibrosis in CHB patients. Studies have shown elevated serum GP73 levels in the presence of HBV infection, liver fibrosis, cirrhosis, or HCC, further supporting our results.
Compared to other NITs, PRO-C3 is superior to FIB-4 and comparable to LSM in diagnosing significant and advanced fibrosis. When combined with GP73, its efficacy in diagnosing significant fibrosis in CHB patients significantly exceeds that of LSM, FIB-4, and APRI. Although FIB-4 and APRI are more accessible, studies have shown their moderate accuracy in diagnosing liver fibrosis in CHB patients. Compared to LSM, PRO-C3 and GP73 are more convenient and accessible, as they are measured using serum ELISA. For primary medical centers with limited resources and/or where transient elastography technology is not yet widespread, PRO-C3 and GP73 are viable non-invasive diagnostic methods.
