Angiopoietin-2 Serum Levels Improve Noninvasive Fibrosis Staging in Chronic Hepatitis C: A Fibrogenic-Angiogenic Link

Abstract

Aims: Accurate liver fibrosis staging is crucial for the management of chronic hepatitis C (CHC). The invasiveness and cost burden of liver biopsy have driven the search for new noninvasive biomarkers of fibrosis. Based on the link between serum angiopoietin-1 and 2 levels and CHC progression, we aimed to determine the value of these angiogenic factors as noninvasive biomarkers of liver fibrosis.

Methods: Serum levels of angiopoietin-1 and -2 were measured by ELISA in 108 CHC patients who underwent pretreatment liver biopsy. The correlation between angiopoietins and clinical and demographic variables with liver fibrosis was analyzed by univariate regression. Significant factors were then subjected to multivariate analysis, from which we constructed a novel noninvasive liver fibrosis index (AngioScore), whose performance was validated in an independent series of 71 CHC patients. The accuracy of this model was compared with other documented fibrosis algorithms by De Long test.

Results: Angiopoietins correlated significantly with hepatic fibrosis; however, only angiopoietin-2 was retained in the final model, which also included age, platelets, AST, INR, and GGT. The model was validated and behaved considerably better than other fibrosis indices in discriminating all, significant, moderate and severe liver fibrosis (0.886, 0.920, 0.923). Using clinically relevant cutoffs, we classified CHC patients by discarding significant fibrosis and diagnosing moderate and severe fibrosis with greater accuracy, sensitivity, and specificity.

Conclusions: Our novel noninvasive liver fibrosis model, based on serum angiopoietin-2 levels, outperforms other indices and should help substantially in managing CHC and monitoring long-term follow-up prognosis.

Figure 1. Serum levels of Ang1 and Ang2 in the training set of 108 CHC patients.

Distribution of Angiopoietin-1 (A), Angiopoietin-2 (B), and Ang2/Ang1 (C) serum concentrations against METAVIR fibrosis stage. Medians are represented by horizontal lines. Two-sided p-values were calculated by non-parametric Mann-Whitney U Test.

Figure 2. Performance of serum angiopoietin level in the training set of CHC patients.

The area under the receiver operating characteristic curves (AUC-ROCs) of Ang1, Ang2, and Ang2/Ang1 for significant fibrosis (A), moderate fibrosis (B), and severe fibrosis-cirrhosis (C), respectively, are shown in brackets (n = 108).

Figure 3. Clinically relevant criteria of a novel noninvasive liver fibrosis index, AngioScore.

Diagnostic criteria of AngioScore obtained from the total cohort of CHC patients (n = 178). A) Corrected optimal cutoffs for diagnosing F>1, F>2, and F>3. B) Cutoffs obtained for sensitivities and specificities above 90%. Criteria for excluding F>1 and identifying F>2 and F>3 are shown in bold. n: number of patients in the corresponding category; WC: well-classified patients.