Application of Serum Golgi Protein-73 in the Management of Chronic Liver Disease
Chronic liver disease (CLD) is a significant global health burden, responsible for approximately 2.14 million deaths annually. The primary contributors to CLD-related mortality include chronic hepatitis B (CHB), hepatitis C, alcohol-related liver disease, and non-alcoholic fatty liver disease (NAFLD), accounting for 29%, 26%, 25%, and 9% of cirrhosis-related deaths worldwide, respectively. While vaccination efforts have reduced the prevalence of hepatitis B surface antigen and liver-related mortality, CHB remains a leading cause of liver disease, particularly in China. Meanwhile, the prevalence of NAFLD has surged globally, including in China. The evaluation of liver fibrosis, especially in hepatitis C virus (HCV) infections, is crucial for managing and prognosticating CLD. Although liver biopsy is the gold standard for assessing inflammation and fibrosis, its invasive nature and potential for sampling errors limit its routine use. Consequently, circulating biomarkers have emerged as attractive, non-invasive alternatives for monitoring liver inflammation and fibrosis.
Golgi protein-73 (GP73), also known as Golgi membrane protein-1 (GOLM1), is a transmembrane glycoprotein with a molecular weight of 73,000. Initially cloned from the liver of a patient with adult giant-cell hepatitis, GP73 is predominantly expressed in bile duct epithelial cells and minimally in hepatocytes in healthy livers. Early studies suggested that serum GP73 could serve as a diagnostic marker for hepatocellular carcinoma (HCC). However, recent research indicates that serum GP73 levels in HCC patients are comparable to or even lower than those in CLD patients with cirrhosis. Specifically, elevated serum GP73 is observed in HCC patients with cirrhosis but not in those without cirrhosis. Immunohistochemical analysis further supports this, showing high GP73 expression in dysplastic nodules of cirrhotic HCC patients but low expression in non-cirrhotic HCC tissues. These findings suggest that serum GP73 is not a reliable biomarker for distinguishing HCC from cirrhosis. Instead, it appears to correlate more closely with the severity of cirrhosis, as evidenced by its unchanged levels post-tumor resection and its positive correlation with cirrhosis severity.
The diagnostic potential of serum GP73 for cirrhosis was evaluated in a large cohort of 3,044 patients, including those with compensated cirrhosis, decompensated cirrhosis, and pre-cirrhotic CLD. The area under the curve (AUC) for serum GP73 in diagnosing compensated cirrhosis was 0.909, outperforming the aspartate aminotransferase-to-platelet ratio index (APRI) and the fibrosis index based on four factors (FIB-4), and comparable to liver stiffness measurement (LSM). Receiver operating characteristic (ROC) analysis further validated serum GP73 as a reliable serological indicator of liver fibrosis severity. To enhance its diagnostic accuracy, researchers combined serum GP73 with LSM, achieving superior diagnostic performance for significant liver fibrosis in CHB patients, thereby reducing the need for liver biopsies. Additionally, the GAPA model, which integrates serum GP73 with age, platelet count, and alkaline phosphatase activity, demonstrated excellent diagnostic performance for cirrhosis, further solidifying GP73’s role in fibrosis assessment.
Beyond fibrosis, serum GP73 also reflects liver inflammation, a critical factor in CLD progression. Moderate-to-severe inflammation and fibrosis are key triggers for intervention, as recommended by clinical guidelines. Serum GP73 has shown promise as an auxiliary biomarker for moderate liver necroinflammation, particularly in CHB patients with normal alanine aminotransferase (ALT) levels. The hepatic inflammation model (HIM), which combines serum GP73, gamma-glutamyltransferase, and aspartate aminotransferase, exhibited an AUC of 0.890 for diagnosing liver necroinflammation, outperforming individual biomarkers. This model also effectively identified patients with moderate liver necroinflammation and ALT levels below 40 U/L. Similarly, combining ALT and GP73 enabled the identification of 77.4% to 78.9% of patients with significant liver lesions. In chronic HCV infection, serum GP73 proved useful for monitoring disease progression, although its diagnostic value for advanced fibrosis and cirrhosis was limited compared to APRI and FIB-4.
In the context of NAFLD, serum GP73 has emerged as a valuable biomarker for hepatic necroinflammation, particularly in non-alcoholic steatohepatitis (NASH). Studies have shown that serum and liver GP73 levels are elevated in NASH patients with high necroinflammation grades, correlating strongly with inflammation severity. The AUC for serum GP73 in diagnosing moderate inflammation (G ≥ 2) was 0.742, surpassing ALT (0.609) and AST (0.667). For severe inflammation (G ≥ 3), serum GP73 achieved an AUC of 0.891. The G-NASH model, combining GP73 and CK18-M30, demonstrated superior diagnostic accuracy for NASH compared to other non-invasive scoring systems, correctly identifying 82.9% of NASH patients.
The mechanisms underlying increased GP73 expression during liver inflammation remain incompletely understood. However, studies suggest that interleukin-6 (IL-6) plays a key role. In a lipopolysaccharide-induced mouse liver injury model, hepatic GP73 expression increased following IL-6 upregulation, and this increase could be inhibited by blocking IL-6 or its downstream signaling pathway. These findings propose a model where liver inflammation triggers IL-6 production, which then enhances GP73 expression via the STAT3 signaling pathway. Additionally, furin, the enzyme responsible for GP73 protein processing, is upregulated by IL-6, facilitating the release of GP73 into the serum.
In summary, serum GP73 has significant potential as a biomarker for liver fibrosis, cirrhosis, and inflammation in various CLD etiologies. Its diagnostic accuracy, particularly when combined with other biomarkers or imaging techniques, offers a non-invasive alternative to liver biopsy. However, further research is needed to fully elucidate the mechanisms regulating GP73 expression and to validate its clinical utility in large, multi-center studies. Prospective studies are also warranted to explore its role in predicting temporal changes in liver disease progression.
doi.org/10.1097/CM9.0000000000001296
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