Introduction
Hepatocellular carcinoma (HCC) is considered the sixth most prevalent malignant tumor in the world, and it ranks first in Egypt. Early detection of HCC is of great value, as early stages can be treated with curative modalities. Current surveillance programs depend on ultrasonography with or without alpha-fetoprotein (AFP) measurement, but the ultrasonography is operator-dependent and has many limitations, while AFP is neither adequately sensitive nor specific. Serum Annexin A2 has the potential to be a promising biomarker for the early detection of HCC.
Aims & Methods
The aim of the present study is to evaluate the potential contribution of serum annexin A2 in the detection of hepatocellular carcinoma. This case-control study included four groups:
Group A: Early hepatocellular carcinoma; BCLC stages 0 and A.
Group B: Advanced hepatocellular carcinoma; BCLC Stage C.
Group C: liver cirrhosis without HCC.
Group D: healthy subjects as a control group.
Chronic hepatitis C was the cause of cirrhosis in the three groups (A, B, and C). All of them attained sustained virological response (SVR) after receiving treatment with direct-acting antiviral medications (DAAs). Subjects with other liver cirrhosis causes, those with active hepatitis C viremia, those with combined hepatitis B virus infection, and those with any other malignancy were excluded.
Assuming a common standard deviation (14.6) using the F test (one-way ANOVA power analysis), at significance level.05, a sample size of 100 participants (25 per group) was needed to achieve 80% power to detect an overall difference of at least .35 ng/mL in the mean of serum annexin A2 between the studied 4 groups.
Both serum AFP and annexin A2 were measured in all included subjects.
Results
One hundred subjects were included in the study, 25 in each group. There were no statistically significant differences between groups regarding age and sex. The 3 diseased groups were not statistically significantly different regarding the modified Child-Pugh scores (median was 5), ALBI grading, MELD scores, platelet counts, INR, albumin, and total serum bilirubin levels.
By ROC curve analysis, at a cut-off point >12 (ng/ml), AFP was a statistically significant discriminator between HCC patients (group A+B) and patients with liver cirrhosis (group C), with an area under the ROC curve (AUC) = 0.670 (95% CI 0.550 to 0.789) (p =.017), sensitivity of 60.00%, specificity of 76.00%, positive predictive value (PPV) of 83.30%, and negative predictive value (NPV) of 48.70%, but at the same cut-off point, AFP is not a statistically significant discriminator between patients with early HCC (group A) and patients with liver cirrhosis (group C) with an AUC of 0.619 (95% CI 0.450 to 0.783) (p =.148), with a sensitivity of 52.00%, a specificity of 76.00%, a PPV of 68.40%, and a NPV of 61.30%.
Serum annexin A2 levels showed a significant difference between the advanced HCC and the early HCC groups compared to the group of healthy individuals (group D) (p<.001). Annexin A2 levels were also significantly higher between the early HCC and advanced HCC groups when compared to the cirrhosis-only group (p =.005 and p<.001, respectively). Moreover, annexinA2 levels were significantly higher in the advanced HCC group when compared to the early HCC group (p =.003). Annexin A2 was also higher in the cirrhosis-only group than in the healthy group (p =.002).
By ROC curve analysis, at a cut-off point >7.7 (ng/ml), serum annexin A2 was a statistically excellent discriminator between HCC patients (group A+B) and patients with liver cirrhosis (group C) with an AUC of 0.962 (95% CI 0.910 to 1.000) (p<0001), with a sensitivity of 98.00%, a specificity of 88.00%, a PPV of 94.2%, and a NPV of 95.7%. At the same cut-off point, annexinA2 is a statistically significant discriminator between patients with early HCC (group A) and those with liver cirrhosis (group C), with an AUC of 0.934 (95% CI 0.851 to 1.000) (p >.001), a sensitivity of 96.00%, a specificity of 88.00%, a PPV of 88.90%, and a NPV of 95.7%.
Conclusion
Serum annexin A2 is a promising biomarker that can improve the sensitivity of HCC detection among patients with liver cirrhosis after HCV eradication using DAAs.