Serum angiopoietin 2 acts as a diagnostic biomarker for hepatocellular carcinoma: a meta-analysis of diagnostic test accuracy studies.

Abstract

Background & Aims: HCC is characteristically a hypervascular tumor where angiogenesis is directly linked to its progression. Angiopoietin-2 (Ang-2) promotes vascular remodeling as the Ang-2-Tie2 pathway suppresses interactions between endothelial cells and vascular mural cells: pericytes and vascular smooth muscle cells. However, the importance of Ang-2 has a controversial outcome between the studies, thus we aimed to systematically analyze the diagnostic utility of serum Ang-2 in patients with HCC in comparison with cirrhotic liver diseases. Methods: We searched PubMed, Scopus, Embase, and Web of Science databases until Jan 2022, to identify studies assessing serum levels of Ang-2 in patients with HCC. Studies that measured Serum Angiopoietin 2 levels of hepatocellular carcinoma patients, articles that were published in peer-reviewed international journals and had enough data for qualitative and quantitative analysis were included with no language restriction. We conducted our double-arm meta-analysis using the “meta” package in R version 4.1.0. Random-effects meta-analysis models were employed to estimate the pooled serum level on angiopoietin 2 level. The data was continuous, we used the mean difference with a 95% confidence interval to assess the estimated effect measure. A leave-one-out meta-analysis was performed to show how each individual study affects the overall estimate by removing one study alternately from the meta-analysis. Results: Ten studies with 3175 patients met our criteria and were included in our meta-analysis. The serum level of Ang-2 was higher in the HCC group when compared to healthy participants, Chronic liver disease patients or patients with liver cirrhosis. Ang-2 as a marker was compared between HCC and healthy participants with significant favor for HCC (p=0.00001). The cumulative mean difference was significant at 2.88 (95% CI of 1.87, 3.89). Furthermore, Ang-2 as a marker was compared between HCC and cirrhotic liver patients with significant favor for HCC (p=0.003) with significant mean difference(MD) 2.52 (95% CI of 0.85, 4.18), while when compared between HCC and Chronic liver disease patients revealed a significant favor for HCC (p=0.0002) with MD 1.93 (95% CI of 0.92, 2.93).The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio were 0.79, 0.89, 9.86, and 0.08, respectively. The summary ROC plot showed an area under the curve (AUC) of 0.9816 and Q*=0.9403. Conclusion: Having both high pooled sensitivity and specificity, serum Ang-2 shows the potential to have a vital role as an independent diagnostic marker in HCC over decades of other biomarkers used.